IL87037A

IL87037A - 3-Demethyl-4-fluoromevalonic acid derivatives, a process for the preparation thereof, pharmaceutical products based on these compounds, and the use thereof

Info

Publication number: IL87037A
Application number: IL8703788A
Authority: IL
Original assignee: Hoechst Ag
Priority date: 1987-07-10
Filing date: 1988-07-08
Publication date: 1995-03-30
Also published as: NO172537B; NZ225345A; US4898868A; ZA884922B; DK383388A; EP0302253B1; FI883250A0; FI883250A; KR890002084A; NO883074D0; DK383388D0; ATE87916T1; PT87930A; AU612665B2; JPS6438086A; HUT51221A; DE3880041D1; NO883074L; AU1888388A; PH26770A

Abstract

3-Demethyl-4-fluoromevalonic acid derivatives, a process for the preparation thereof, pharmaceutical products based on these compounds, the use thereof, and intermediates 3-Demethyl-4-fluoromevalonic acid derivatives of the formula I, and the corresponding dihydroxy carboxylic acid derivatives of the formula II <IMAGE> in which R, X and Y have the stated meanings, processes for the preparation of these compounds, the use thereof as medicaments, and pharmaceutical products are described. In addition, new intermediates for the preparation of the compounds of the formula I and formula II are described. [US4898868A]

Description

* 3-DEMETHYL-4-FLU0R0MEVAL0NIC ACID DERIVATIVES, A PROCESS , FOR THE PREPARATION THEREOF, PHARMACEUTICAL PRODUCTS BASED ON' . THESE COMPOUNDS, THE USE THEREOF, .AND INTERMEDIATES . ■ ,η·>3Ί!?ιιαΐ ΊΝνί?ο - l»nm - *3 nunm ¾ nn!nn ,ni>N y D oo"i3nn riinpii ^ eon .onioni? no i>> . ·; ,ρ·»·»3·> ΐήο-irn ona nn n j 3-D erne t h y I -4- f L uo r ome v a L on i c ac i d de r i v a t i ves, a process for the preparation thereof, ph armaceuti c a L produc ts based on these compounds, the use the r eof , H percholesterolemia is one of the ess en tial primary risk factors for one of the commo nest c a r d i 0 V ascular disor -ders, atherosclerosis (Kanne I et a I., Am . Intern. Med • 74 (1971), 1). Influencing the ac t i v i ty of the key enzyme of human cholesterol b iosyn t hes i s , HMG-CoA red uc-tase, is thus nowadays regar ded as a r at ional way of discovering new medicaments or th e t r ea tment of athe r o-sclerosis.

In 1976, Endo et al. (J. Antibiotics, 9 (1976) 1346) and Brown et al. (J. Chem. Soc. Perkin I 1976, 1165) found a potent competitive inhibitor of HMG-CoA reductase in the culture broths of microorganisms, called compactin, a derivative of 3-demethylmevalonic acid.

German Of f en I egung s s c h r i f t 3,530,798 (corresponds to EP-A 0,216,127; US Patent Appl ication Serial No. 900,848) describes compactin derivatives which carry phenoxy radicals substituted in the 6 position. German OffenLegungsschrift 3,530,797 (corresponds to EP-A .0,217,092; US Patent Appl ication Serial No. 900,887) describes compactin derivatives which carry benzyl or benzyl idene radicals suitably substituted in the 6 position, and the free carboxyl ic acids, esters and salts thereof . German OffenLegungsschrift 3,632,893 proposes compactin derivatives which are Linked at C-6 to substituted thiophen-oxy, and the sulfoxides and sulfones thereof, as inhibitors of HMG-CoA reductase. - ΐ - 87037/2 In French Patent Application No. 2,392,016 there are disclosed certain compounds, which have a certain similarity with compounds of the present invention of Formula I wherein the group R - X - Y has Formula IV wherein R7 -Z is phenyl or substituted phenyl.

Compounds 8, 19, 21, 28 and 58 of the French application are the ones closest to the present invention. The inhibitory value ICso of compound 44 of the present application is 9.8 x 10_θ whereas the corresponding values of the compounds of said French application are lower by a factor of about 1,000. This is a surprising activity which could not be predicted on the basis of the French Application.

Although it is known that slight changes in the subst tution pattern of the compactin Lactone skeleton may suit in drastic decreases in the inhibitory effect on HMG-CoA reductase (for example Stokker et al., J. Org.

Chem. 5_ ( 1986) 4931, or European Patent Application EP-A 0,142,146), we have now found, surprisingly, that, in the case of compactin analogs which have a fluorine atom in the 4 position of the lactone skeleton, these compounds have a potent inhibitory effect on cholesterol biosynthesis.

Hence the present invention relates to 3-deme t hy I -4-f I uo ro-mevalonic acid derivatives of the general formula I and to the corresponding free dihydroxy carboxyl ic acids of the f ormul a II and to the pharmaceutically utilizable salts and esters thereof . In formula I or II, Y-X-R denotes A) the group of the formula - 3 - in which Y-X is the CHgO or C H 2 S group, and R and R are identical or different and denote a) hydrogen or halogen, b) cycloalkyl having 4-8 carbon atoms or a phenyl radical which can be substituted in the nucleus 1 to 3 times by halogen, tr i luoromethyl and/or alkyl or alkoxy, each having 1-4 carbon atoms, or c ) a straight-chain or branched alkyl radical ha ing 1 to 18 carbon atoms or a straight-chain or branched alkenyl radical having 2 to 18 carbon atoms, it being possible for the alkyl and alkenyl radicals in turn to be substituted 1-3 t imes by a) s t r a i g h t - c h a i n or branched alkoxy radicals having up to 10 carbon atoms, or cycloalkoxy radicals having 3 to 7 carbon atoms, or s t r a i gh t-c h a i n or branched alkenyloxy or alkynyloxy radicals having 3 to 6 carbon atoms, B) halogen, hydroxyl, cycloalkyl having 3-7 carbon atoms, unsubs t i tuted phenyl or a- or β-thienyl radicals, or phenyl or o- or β-thienyl radicals which in turn are substituted in the nucleus 1 to 3 times by halogen, t r i f I uorome t hy I and/or alkyl or alkoxy having 1 to 4 carbon atoms, γ) unsubs t i tuted phenoxy, benzyloxy, or a- or β-thienyl- oxy radicals, or phenoxy, benzyloxy or a- or β-thie- nyloxy radicals which in turn are substituted in the nucleus 1 to 3 times by halogen, t r i f I uo r bme t hy I and/or alkyl or alkoxy having 1 to 4 carbon atoms, 0 ) the group -O-C-R^, where R^ denotes: a straight-chain or branched alkyl or alkenyl radical having up to 8 carbon atoms, or a cycloalkyl or cyclo- alkenyl radical, each of which has 3-8 carbon atoms, or an unsubs t i tuted phenyl radical, or a phenyl radical which in turn is substituted in the nucleus 1 to 3 times by halogen, tr i f luoromethyl and/or alkyl or alkoxy having 1-4 carbon atoms, or a 3-pyridyl radical, - 4 - R 2 and R 4 are identical or different and denote hydrogen, alkyl having 1-4 carbon atoms, halogen or alkoxy having 1-4 carbon atoms, and R^ denotes hydrogen, halogen, alkyl or alkenyl having up to 4 carbon atoms, alkoxy having 1-4 carbon atoms, or phenyl which can be substituted 1-3 times by halogen or C1-C4 alkyl, B) the group of the formula IV which X - Y is equal to CH=CH or CH2-CH2, represents a single bond or CHg, and denotes a eye loal iphat i c hydrocarbon radical having 3 to 7 carbon atoms, a phenyl radical which can be substituted in the nucleus 1 to 3 times by halogen, tri luoromethyL, alkyl or alkoxy, each having 1 to 6 carbon atoms, or by hydroxymethy I , or denotes a furyl, thienyl or pyridyl radical, it being possible for the heteroaromatic radicals to be substituted 1 to 2 times by halogen, trifluoromethyL, alkyl or alkoxy, each having 1 to 6 carbon atoms, and o and R denote hydrogen, halogen, trifluoromethyL, or alkyl or alkoxy, each having 1 to 6 carbon atoms, group of the formula in wh i ch X-Y is equal to CH=CH or CH2-CH2 is equal to CH or N, and denotes H, s t ra i gh t -c ha i n C -j - a I k y I , branched C3-C$-alkyl , tr i f luoromethyl perf luoroisopropyl , denotes H, s t r a i g h t - c h a i n C 1 -C 4-a I k I , branched C^-C^-al kyl , cyc loal kyl having 5-8 r ing carbon atoms, phenyl wh i ch can be subs t i tuted 1 or 2 t by stra ight-cha in C <|-C3-al kyl , C 1 - C 3- a I k 0 x y , halogen or by tr i f luoromethyl denotes H, s t r a i g h t - c h a i n C 1 -C_;-a I ky I , branched C^-C^-alkyl, cyc loal kyl hav ing 5-8 r ing carbon atoms, phenyl wh ich can in turn be subs t i tuted 1 or 2 t imes by s t r a i g h t - c h a i n C -] - C 3-a I k y I , tr i f luoromethyl , hydroxyl or by halogen, D ) the group of the formula VI in wh i ch X-Y is the CH=CH or CH2-CH2 group G-E denotes the fol lowing sequences of atoms a) N -c ( 1H -pyrrol-2 -yl ) b) S -c (2- th ienyl ) c ) C -N ( 1H -pyrrol-3 -yl ) d) C -0 (3- fury I ) e) C -S (3- t h i en I ) 13 denotes H, s t r a i gh t -c ha i n C -|-C4-alkyl , branched C^-C^-alkyl , tr if luoromethyl , halogen or phenyl wh i ch is opt ional ly subst ituted 1-2 t imes by f luor ine, chlor ine or methyl , eno es , s t r a g t - c a n C 1 -C - a I y l , ranched f^-C^-alkyl, t r i f I uo r ome t h y L , halogen or phenyl, R denotes H, cycloalkyl having 5-8 ring carbon atoms, branched f^-C^-alkyl, or phenyl which can in turn be substituted 1-2 times by straight-chain C -j - C 3 - alkyl, halogen or t r i f I uo r ome t h y I , and 6 R denotes H, s t r a i g h t - c h a i n C 1 -C 3-a I k y I , branched C^-C^-alkyl, cycloalkyl having 5-8 ring carbon atoms, t r i f I uo r ome t h I , or phenyl which can in turn be substituted 1-2 times by s t r a i g h t - c h a i n C 1 - C 3 - alkyl, halogen or t r i f I uo r ome t h y I , and 1 16 R and R together also denote a conjugated unsaturated 1 L 1 A radical having A carbon atoms, so that R and R form a fused-on aromatic system^ as well as the pharmaceutically utilizable salts and esters thereof.

The passages which Uo not fall within the scope of the claims do not belong to tlie invention. The scope of the protection Is as defined by tlie claims and according to the stipulations of the Patent Law (1968).

The substituents R and R are absent from those he te roa r oma t i c compounds which have oxygen or sulfur in the corresponding positions.

The invention relates to the pure enantiomers with the absolute configuration 3S, A R or AS, 5R indicated in the general formula I, with the open-chain carboxylic acids of the formula II which can be obtained therefrom, and the esters and salts thereof, having the same absolute conf igurat ion.

Pharmacologically tolerated salts of the appropriate dihy droxy carboxylic acids of the general formula II which may be mentioned are alkali metal salts or ammonium salts examples of pharmaceutically acceptable esters are alkyl esters having 1 to A carbon atoms, phenyl esters, benzyl esters or else 2 , 3-d i hy d r oxy p r opy I esters.

If Y-X-R denotes the group of the formula III, the substituents preferably have the following meanings: Y equal t6 OCH2 or S-CH2 5 and R , identical, or different: hydrogen or halogen, cycloalkyl having 5 to 6 carbon atoms, phenyl which can be substituted in the nucleus 1-3 times by halogen, t r i f I uo rome t h I and/or alkyl or alkyloxy, each having 1-4 carbon atoms, or 1. straight-chain or branched alkyl or alkoxy having up to 12 carbon atoms, it being possible for the alkyl or alkenyl radical in turn to be substituted 1-2 times by phenyl radicals which, in turn, can be substituted in the nucleus 1 to 3 times by halogen, t r i f I uo r ome t hy I and/or alkyl or alkoxy having 1-4 car bon atoms, 2. straight-chain alkyl substituted by O-C-R^ of the in which n denotes 1 to 3, and R denotes a straight- chain or branched alkyl or alkenyl radical having up to 8 carbon atoms, a cycloalkyl radical having 5 to 6 carbon atoms, or a phenyl radical which in turn can be substituted in the nucleus 1-3 times by halogen, trrf luoromethyl and/or alkyl or alkoxy having 1 to 4 carbon atoms, 3. straight-cha n alkyl substituted by OR^, of the formula 17 -(CH2>n0R in which n denotes 1 to 3, and R denotes hydrogen or a straight-chain or branched alkyl or alkenyl radical having up to 8 carbon atoms, a cycloalkyl \ - 8 - radi cal having 5 to 6 carbon atoms or a phenyl radical or benzyl radical , each of wh i ch can in turn be subst i tuted in the aromat i c nucleus 1-3 t imes by halo gen, tr if luoromethy I and/or al kyl or alkoxy having 1 to A carbon atoms, 2 R and R hydrogen, R ^ hydrogen, methyl , ethyl , propyl , i sopropyl , t-butyL , 1-propenyl, al lyl , f luor ine or chlor ine .

The part i cularly preferred mean ings of the subst i tuents X-Y = SCH 1 5 1 5 R and R , wi th R and R be ing ident ical or di f ferent 1 ) hydrogen, methyl , ethyl , propyl , al lyl , 1-propenyL, t-butyl , isopropenyl , isopropyl , cyc lopentyl , cyc lo- hexyl, p- I uoropheny I , p-c h I o r op h eny I , 3-methyl-4- f luorophenyl 0 " 6 6 2) the group - ( C ) n0-C-R , wi th n = 1 - 3, where R denotes : methyl , ethyl, propyl , i-propy , n-butyl , i-butyl , t-butyl , phenyl or phenyl wh i ch is subst ituted in the nuc leus 1 to 3 t imes by halogen, methyl or methoxy, or 3) the group -( CH2 >nOR17, wi th n = 1 to 3, where R 7 denotes : hydrogen, methyl , stra ight-chain or branched al kyl or al kenyl hav ing 3 to 5 carbon atoms, cyc lopentyl, cyc lohexyl ; phenyl or benzyl , i t being poss ible for the aromat i c nuc lei to be subst i tuted 1 to 3 t imes by f luor ine, chlor ine, methyl or methoxy or 4) an alkyl group of the formul a -( CH2)n,CHR 18R19 - 9 - 18 19 in which m is 0 to 2, and R and R are identical or different and denote hydrogen, methyl, ethyl, propyl, a lyl, i-propyl, n-butyl, i-butyl, t-butyl, cyclohexyl, cyclopentyl, benzyl or phenyl, it being possible for the aromatic nuclei to be substituted 1 to 3 times by fluorine, chlorine, methyl or ethoxy, 2 4 R and R hydrogen R hydrogen, methyl, chlorine, fluorine or p-fluoro- pheny I .

B) If Y-X-R denotes the group of the formula IV, the substituents preferably have the following meanings: X-Y: CH=CH or CH2-CH2, Z = single bond R^: cyclopentyl, cyclohexyl or a phenyl radical which can be substituted in the nucleus 1 to 3 times by halogen, trifLuoromethyl, hydroxymethy I , alkyl or alkoxy, each having 1 to 4 carbon atoms, a furyl, thienyl or pyridyl radical, it being possible for the heteroaromat i c radicals to be substituted 1 to 2 times by halogen, trifLuoromethyl, alkyL or aLkoxy, each having 1 to 4 carbon atoms, R 8 , R 9 : hydrogen, halogen, trifLuoromethyl, alkyL or aLkoxy, each having 1 to 4 carbon atoms.

Among the substituents R^, those Listed below are particularly preferred: cyclopentyl, cycLohexyl or an un s ub s t i t u t ed phenyl radical, or phenyl which is substituted once or 3 times by halogen, trifLuoromethyl, hydroxymethy I , Ci-C4~alkyl or C 1 - C - a I koxy, or a furyl, thienyl or pyridyl radical, it being possible for the hetero- aromatic radicals to be substituted once or 2 times by halogen, trifLuoromethyl, C-j-C^-aLkyL or C -j - C - - 10 - a I k o x y , especially the radicals: cyclopentyl, cyclohexyl, phenyl, 4- c h I o r oph eny I , 2- c h I oropheny I , 3- c h I o r op heny I , 4-bromopheny I , 4-fluoro-phenyl, 4-me t h y I p h e n y I , 3- t r i I uo r ome t h y I ph eny I , 4- t r i f I uo r ome t h y I ph e n y I , 4-me t ho x y p h eny I , 3-methoxy-phenyl, 3-me t h y p h e n y I , 3 , 4 , 5 - t r i me t ho y ph e ny I , 3-furyl, 2-furyl, 2-thienyl, 3-thienyl, 3-pyridyl, 4-pyridyl, 2 , 6-d i me t h y I -4-py r i dy I , 3-h y d r ox y me t h y I -phenyl, 3-ethy Ipheny 1 , 3- i s op r op y I p heny I , 3-isobutyl-phenyl, 3- 1 e r t . -bu t y I pheny I , - c h I o r o-3- 1 h i eny I . 8 9 Among the substituents R and R , those particularly preferred are: hydrogen, 2-methyl, 2- 1 r i f I uo r ome t h y I , 2 , 4-d i me t y I , 2,4-bistrifluoromethyl, 2-ethyl, 2-isopropyl, 2-iso-butyl, 2-chloro, 2-fluoro, 2-bromo, 2 , 4-d i c h I o r o, 2,4-difluoro, 2-methoxy, 4-methoxy, 2,4-dimethoxy.

If Y-X-R denotes the group of the formula V, those among the substituents which are preferred are: equal to CH=CH or CH2-CH2, A equal to CH or N H, halogen, t r i f I uo r ome t h y I , s t r a i gh t - c h a i n alky having 1 to 4 carbon atoms and branched alkyl having 3 to 4 carbon atoms. cyclopentyl, cyclohexyl, or phenyl which can be substituted 1 or 2 times by fluorine, chlorine, straight-chain C-j-C3-alkyL or t r i f I uo r ome t h y I . methyl, branched C3-C5-alk l, cyclopentyl, cyclohexyl or phenyl which can in turn be substituted 1 or 2 times by methyl, t r i f I uo r ome t hy I , chlorine or fluorine. - 11 - Among the substituents R 10, those particuLarLy preferred are: methyl, isopropyl, t r i f I u r ome t h y I , chlorine and fluorine.

Among the substituents R , those particularly preferred are: cyclohexyl, phenyl, 4- luorophenyl , 3- me t h y I -4- f I uo roph eny I , 2 - c h I o r op h en y I , 3- c h I o r op h eny I , 4-c h I oropheny I , 2-me t h y I p h e n y I , 3-me t h y I ph eny I , 4- methylphenyl, 3-methyl-4-trifluoromethylphenyl.

Among the substituents R , those particularly preferred are: methyl, t r i f I uo r ome t h I , isopropyl, iso- butyl, cyclopentyl, cyclohexyl, phenyl, 4-fluoro- phenyl, 3-me t h y I -4-f I uo r op h eny I , 2- c h I o rop h eny I , 3- c h I oropheny I , 4- 1 r i f I uo r op h e ny I .

D) If Y-X-R denotes the group of the formula VI, the following meanings are preferred X-Y the CH=CH or -CHg-C^-group, G-E the sequence of atoms as in c) and e) Among the substituents R 13 , those preferred are: H, methyl, ethyl, propyl, isopropyl, t-butyl, t r i f I uo r ome t h y I Among the substituents R 14 , those preferred are: straight chain t r i f I uo r ome t h y I and phenyl.

Among the substituents R 15 , those preferred are: cyclo-alkyl having 5 or 6 ring carbon atoms, and phenyl which can in turn be substituted 1 or 2 times by methyl, ethyl, chlorine, bromine, fluorine or trifluoromethyl. 16 Among the substituents R , those preferred are: straight chain C^-C3-alkyl, branched C3-C$-alkyl, trifluoromethyl, or phenyl which can in turn be substituted 1 or 2 times by methyl, ethyl, propyl, trifluoromethyl, chlorine or fluorine. - 12 - Among the substituents R 13 , those mentioned hereinafter are particularly preferred: methyl, isopropyl, tertiary-butyl and t r i f I uo rome t hy I .

Among the substituents R 14 , those particularly preferred are: methyl, isopropyl, tertiary-butyl, trifluoromethyl and phenyl.

Among the substituents R 15 , those particularly preferred are: cyclohexyl, phenyl, 2-me t hy I ph eny I , 3-me t h y I p h eny I , 4-methylphenyl, 4-fluorophenyl, 3-fluorophenyl, 2-fluoro-phenyl, 3-me t h y I -4- f I uo rop heny I , 2-me t hy I -4-f I uo r ophe n y I , 4-trifluoromethylphenyl, 3-trifluoromethylphenyl, 2-tri-fluoromethylphenyl, 3-trifluoromethyl-4-fluorophenyl, , 4-d i c h I oropheny I , 2-me t h y I -4-c h I orophen I , 3-me t hy I -4-chlorophenyl .

Among the substituents R 16 , those particularly preferred are: methyl, isopropyl, tertiary-butyl, trifluoromethyl, phenyl, 4-fluorophenyl, 4-trifluoromethylphenyl, 3-methyl-4-f luoropheny I and 2 , 4-d i c h I o rop h e ny I .

The invention also relates to a process for the preparation of compounds of the general formula I or II, which comprises the fluoro synthon of the general formula VII in which R 20 denotes a protective group which is stabl to bases and weak acids, preferably benzyl, p-methoxy-benzyl or t-bu t y I d i phen I s I y I , R^ denotes an acetal tective group which can be eliminated with weak acid, such as benzyl, methyl or ethyl, and the fluorine atom has either the R or the S configuration, being reacted with phenol 6—O-P- t h i opheno I s of the general f ormul a - 13 - in which R to R have the meaning indicated for formula ί , and X denotes oxygen or, sulfur, to give the ethers of the formula IX where R to R have the meanings indicated for formula I, R^ and R^ have the meanings indicated for formula VII, and X has the meanings indicated for formula VIII, the ethers of the formula IX being hydrolyzed to give the correspond ng hemiacetals of the formula in which R to R the meanings indicated for formula I, and R has the meanings indicated for formula VII and X has the meanings indicated for formula VIII, - 1 A -c) the hemiacetals of the formula X being oxidized to give the corresponding Lactones of the formula XI in which R' to d for formula I, and R^ has the meanings indicated for formula VII, and X has the meanings indicated for formula VIII, and d) the protected hydroxy lactones of the formula XI being converted into the compounds of the formula I (Y-X-R = group of the formula III) where appropriate the resulting compounds of the formula I being converted into the corresponding open-chain dihydroxy carboxylic acids of the for¬ I I - 15 -or the salts thereof or the esters thereof, where appropriate resulting salts or esters being converted into the free dihydroxy carboxyl ic acids or, where appropriate, the free carboxyl ic acids being converted into the salts or esters, being reacted with tr iphenylphosp ine to give the phosphonium salts of the formula Xll XII in which R^ and R^ have the meanings indicated for formula VII, the phosphonium salts of the formula XII being con verted in a Wittig reaction with aromatic aldehyde of the formula XIII in which R has the meanings indicated for formula I under B to D, into 4-f luoro-5-arylethene-subst i tuted demethylmevalonic acid derivatives of the formula XIV in which R has the meanings indicated for formula I under B to 0, and R^ and have the meanings indicated for formula VII, - 16 - 21 c) in a compound of the general formula XIV the R acetal function being subjected to acid hydrolysis, and the R 20 protective group being either subjected to acid hydrolysis or removed by oxidation or eliminated by h y d r oge no I y s s to give a lactol of the formula XV R in which R has the meaning indicated for formula I under B to D, d) the compound of the general formula XV being oxidized to give a lactone of the formula I in which R has the meanings indicated for formula I under B to D, e) where appropriate a compound of the general formula I in which Y-X represents a (-CH=CH-) group being hydrogenated to give a compound of the gene- ral formula I in which Y-X represents a (-CH2-CH2-) group, it also being possible for the hydrogenat ion to take place with the compounds of the formulae XIV or XV to give corresponding compounds in which Y-X represents the (-CH2-CH2-) group, where approp- riate a hydroxy lactone I being converted into the corresponding free hydroxy acids II or the salts thereof or, where appropriate, the corresponding ester be ng prepared from the free hydroxy acids II or from the hydroxy lactone I. - 17 - Process 1) is expediently carr ed out under the conditions described in the European patent application with the publication No. 0,216,127. Suitable reaction conditions, especially for the preparation of compounds in which X is sulfur, can also be found in German Patent Application P 36 32 893.6.

The aromatic aldehydes of the formula XIII carry as sub-stituents R the groups which are listed for formula I under. B) to D). Accordingly, they correspond to the follow ing f ormul ae : XIII a XIII b XIII c The phosphonium salts XII in which R and R have the meaning indicated for formula VII are preferably prepared by fusing together the fluoro synthon VII and tri-pheny Iphosph i ne at elevated temperature, preferably 50 ■ 110°C.

The procedure for the Wittig reaction for the preparation of the compound of the general formula XIV is, for example, that of Wittig and Haag, Chem. Ber. 88 (1955) 1654, with a preferred embodiment comprising the phosphonium salts of the formula XII being dissolved or suspended in a solvent such as tet r ahydrof ur an, dimethyl sulfoxide or d i methoxyethane at temperatures between -78°C and -10°C, and the corresponding phosphoranes being liberated with a suitable strong base such as, for example, sodium hydride, potassium t e r t i a ry-bu ty I a t e or bu t y 11 i t h i urn, and then the aldehyde of the formula XIII being added and allowed to react at -60°C to +20°C for 1 to 6 hours. - 18 - The deme t h y L me a L on i c ac id derivatives of the formula XIV are usual ly obtained f rom this in the form of a mixture of the E/Z olef ins wh ich are, where appropr iate, separated by chromatography. The pure Z olef ins can be obtained, as described by 6. Drefahl, Chem. Ber. 9 ^ ( 1967) 907, by irradiat ion of the E/Z mixtures in solvents such as, for example, toluene or nitrobenzene; the corresponding pure E olef ins can be obtained, as described by Oe Tar et al . in J. Am. Chem. Soc. 7J3 ( 1955 ) 474, by heat ing the E/Z mixtures in solution in the presence of iodine.

The compounds of the formula XIV are hydrolyzed, and the protective groups are el iminated, under customary conditions. The compounds of the formula XV are oxidized to give the lactones of the formula I l ikewise under conditions described in the l iterature.

Compounds of the formula I wh ich are obtained and in which X-Y represents a (CH=CH) group can be hydrogenated by general ly customary methods, expediently at temperatures between 20° and 40°C, with hydrogen in the presence of a metal catalyst, preferably palladium, platinum, PtC>2 or Pdn2/ to give compounds of the formula I in which X-Y denotes a (CH2-CH2) group. This hydrogenat ion can be carried out under atmospheric pressure in customary solvents such as tetrahydrof uran, ethyl acetate, low molecular weight alcohols, glac ial acetic ac id, chloroform or cyclohexane, or in autoclaves under elevated pressure at 2 - 50 atm. The hydrogenat ion of the double bond can also take place on precursors.

The fluoro synthons of the formula VII are new and represent valuable intermediates for the preparation of com-pounds of the formula I.

Hence the invention also relates to the compounds of the formula VII as well as to the corresponding unprotected compounds of the formula VII (R^ and equal to - 19 -hydrogen) as well to a process for the preparation of these compounds.

The process for the preparation of compounds of the general formula VII and the corresponding compounds without protective groups comprises a) the glycoside of the formula XVII 21 XVII in which R and R have the meanings indicated for formula VII, being converted into a compound of the formula XVIII XVIII b) the compound of the formula XVIII being acylated with an acylating agent to give a compound of the formula XIX XIX in which R and R have the meanings indicated for - 20 -formula VII, and R i -C Λ - a I k y I group the benzoyl group, and c) 1) either the acyl compound of the formula XIX being reacted with a f luorinating reagent to give a compound of the f ormul a XXa XXa in which R^, R ^ and R^ have the indicated meanings. 2) or the acyl compound XIX being converted, by inver- sion of the conf iguration of the secondary alcohol function in a manner known per se in the presence of 22 an acid carrying R , into a glycoside of the formula XXI XXI the acyl protective groups being removed from a compound of the formula XXI by alkaline hydrolysis, and reg i os e I e c t i ve acylation being carried out to give a compound of the formula XXII - 21 - XXII and the compound XXII being converted by reaction with a fluorinating reagent into a compound of the formula XXb XXb d) the acyl group R 22 being eliminated by customary processes from a fluoro derivative of the formula XXa or b, and the primary alcohol function being converted by customary processes into a primary iodide of the formula Vila or Vllb, for example by preparation of the corresponding p-toluenesulf onates and reaction thereof with sodium iodide, or by the Moffatt reaction, J. Org. Chem. 35 (1970), 2319, with me t h y I t r i ph eno y- phosphonium iodide and, where appropriate, the groups R^^ and R^ being removed by hydrolysis.

Glycosides of the formula XVII are either described in the literature or can be prepared in analogy to described methods (cf., for example, Prugh et al., J. Org. Chem. 1 (1986) 648). Thus, if the synthesis of the glycoside XVII starts from the ct-methy Iglycos ide of the formula XXIII, then the preparation of the fluoro synthon of the formula VII takes places as shown in the following reaction scheme (Scheme 1). - 22 - Scheme 1 XXIII XXIV OHes XXV XXVI XVII XVIII XIX XXI XXII XXa XXb - 23 - The preparation is expediently carried out as described hereinafter. The ct-methyLglycos ide XXIII is - reacted with benzaldehyde dimethyl acetal in an organic solvent, preferably DMF, with acid catalysis, for example para-toluenesulfonic acid or sulfuric acid, under reduced pressure and at elevated temperature (about 60 to 100°C), to give the benzaldehyde acetal XXIV.

- The latter is reacted with me t h ane s u I f ony I chloride in halogenated organic solvents, such as dichlorome- thane, with the addition of tertiary amines such as pyri dine or t r i e t hy I am i ne , to give the methanesulf onate of the formula XXV, and the latter is converted in a base- catalyzed t r anses t e r i f i c a t i on followed by an intramolecular substitution into the epoxide of the formula XXVI (cf. N. . Richtmeyer, C.S. Hudson, J. Am. Chem.

Soc. 63 (1941), 1727), and this epoxide is converted by known processes (A.C. Richardson, Carbohydr. Res. 4 (1967), 422), into the corresponding 3-ct-hydroxy-2- deoxysugar, in which the secondary alcohol is alkylated, for example with benzyl, methoxybenzy I or silyl halides, preferably with p-methoxybenz I chloride or t-bu ty I d i phen I s i I y I chloride by customary methods (J.S. Brimacombe et al. J. Chem. Soc. Perkin I, 1977 643) to give the 2-deoxy-ct-D-al lopy ranos ide XVII. The glycoside of the formula XVII is converted, by removal of the benzylidene protective group under acid conditions (Prugh et al., J. Org. Chem. 5J_ (1986) 5, 652), into the 2-deo x y-3-0-R^-ct-D -me t h y I a 11 os i de of the formula XVIII, which is converted by r eg i os e I e c t i ve acy- lation with acid chlorides or anhydrides, preferably acetic anhydride or pivaloyl. chloride, in inert organic solvents such as diethyl ether, THF, methyl tertiary- butyl ether, DMF, toluene, d i c h I o r ome t h ane or aceto- nitrite, with catalysis by a tertiary base, such as tr iethyla ine or pyridine, into the 3-0-R^-6-0-acy ct-D-methylal los ide of the formula XIX. - 24 - The Latter is converted with a f Luor inat ing reagent, such as sulfur tetraf luor ide or d i a I k y I am i nos u I f u r tri-fluoride (see W.J. Middleton, J. Org. Chem. 40 (1975) 574, Merck-Schuchardt MS-Info 85-7), preferably d i e t hy I am no-sulfur trifluoride (DAST), in an inert organic solvent such as d i c h I o rome t h ane , di chloroethane, 1 , 1 , 1 -d i f I uo r o-chloro-2,2,2-fluorodichlqroethane, tetrahydrofuran, toluene, diethyl ether or methyl tertiary-butyl ether, with the addition of an auxiliary base such as pyridine, t r i e t hy I am i ne or d i i s op r opy I e t h I a m i ne , at elevated temperature, preferably 80°C, into a ( R ) -f I uoro-s ubs t i -tuted compound of the formula XXa, with inversion of the conf iguration of the original (4S)-hydroxyl group.

Inversion of the conf iguration of the secondary alcohol function in compound XIX by the method of Mitsunobu (Bull. Chem. Soc. Japan ^4 (1971) 3427) with conversion into the 4-acetate of the formula XXI, or into the corresponding 4-formate or 4-benzoate, hydrolysis of the protective groups in the compound of the formula XXI by customary methods, preferably sodium methanolate in methanol, where appropriate protection of the 6-hydroxyl group by conversion into the corresponding acetyl or piva-loyl ester of the formula XXII, and f luorination of the ( R ) -hydroxy I group as described above results in the (4S )-f luor inated compound of the formula XXb. From the fluoro derivatives of the formulae XXa and XXb there are obtained, after elimination of the 6-0-acyl protective groups by, for example, customary processes, the primary alcohol functions, and after conversion into the p-t o I uenes u I f ona t es in halogenated solvents, preferably d i c h I o rome t h ane , with catalysis by a tertiary nitrogen base such as pyridine or t r i e t hy I am i ne , and by reaction with inorganic iodide, preferably sodium iodide, in solvents such as acetone or DMF, at temperatures between 50 and 110°C, the iodo lactols of the formula VII. The latter can, where appropriate, be purif ied by chromatography or converted directly by reaction with triphenyl-phosphine, for example in the melt at elevated - 25 - temperatures, preferably 8800 - 110°C, into the phosphon- ium salts of the formula XII Preparation of the starting compounds The phenols of the general formula III with X = oxygen, which are used as starting material, are either described in the literature or can be prepared in analogy to described processes (cf., for example, European patent application with the publication No. 0,216,127).

The thiophenols of the formula VIII with X = sulfur are likewise either described in the literature or can be prepared in analogy to described processes (cf., for example, J. Org. Chem. 3_1_, 3980 ( 1966) and German Patent Application P 36 32 893.6).

The preparation of the substituted aromatic aldehydes of the formula 111 a starts from the corresponding benzyl halides of the formula XXVII XXVII in which R 7 to R 9 and Z have the meaning indicated for formula I, and Hal is chlorine, bromine or iodine. One process for the preparation of benzyl halides of the formula XXVII is described in European patent application with the publication No. 0,217,092. The halides of the formula XXVII are oxidized to the corresponding ben-zaldehydes of the formula Xllla using D S0 in the presence of silver(I) ions and t r i e t hy I am i ne as described by B. Ganem, R . K . Boeckman, Tetrahedron Lett. 1974, 917. The synthesis can also be carried out by the method of S. Murahashi, as described, for example, by G.E. Stokker et al., J. Med. Chem. 29 (1986) 173. - 26 - One process for the preparation of pyridine-3-carbalde-hydes and py r i m i d i ne -5 - c a rba L de hyde s of the general formula X Ϊ 11 b starts from the corresponding h e t a r y I me t h y I alcohol of the formula XXVIII XXVII I in which R to R and A have the meaning indicated for formula V. These alcohols can be obtained from the corresponding esters by reduction with customary reducing agents, preferably Li aluminum hydride. These pyrimi-dine or pyridinecarboxylic esters can be obtained by processes known from the literature [Pyridines by the method of F. Rehberg and F. Krohnke, Liebigs. Ann. Chem. 717 (1968) 91; Pyrimidines: E.F. Silversmith, J. Org. Chem. 27 (1962) 4090]. One process for the preparation of the alcohols of the formula XXVIII is, furthermore, proposed in German Patent Application P 37 22 808.0 of July 10, 1987.

The aldehydes of the formula Xlllb are obtained by oxidation of the alcohols by customary methods, preferably pyridinium chLorochromate in inert organic solvents, preferably d i c h I o r ome t h ane , under the catalytic action of molecular sieves, by the method of J. Herscovici and K . Antonakis (J. Chem. Soc. Chem. Comm. 1980, 561 ).

Heterocyclic aromatic aldehydes of the general formula XIIIc are prepared, for example, by reduction of the corresponding carboxylic esters by customary processes to give the alcohol XXIX CH,OH XXIX - 27 -in which R to R have the meanings indicated for formula I, followed by oxidation thereof to give the aldehyde XIIIc by customary processes such as, for example, in A.J. Mancuso et al., J. Org. Chem. 43 (1978) 2480; the preparation of the carboxylic esters is described in the literature a) for example for G-E equal to S-C: J. . Spragur et al., J. Am. Chem. Soc. 5_6 (1934) 2665; Heterocyclic Com- pounds Vol. 4_4, Part 1, Thiophene and Derivatives, J.

Wiley & Sons, N.Y. 1985, especially page 197; b) G-E equal to C-S: S. Gronowitz et al., Acta pharm. sued. 9 (1972) 301; c) G-E equal to C-0: F. Boberg et al., Liebigs Ann. Chem. 1984, 233; d) G-E equal to C-N: European Patent Application 0,221,025-A 1 or is effected by analogous methods. The preparation of aldehydes of this type is likewise proposed in German Patent Application P 37 22 806.4 of July 10, 1987, and in European Patent Application 0,221,025 A1.

Apart from the compounds described in the examples, it is possible by the process according to the invention to prepare the following compounds: E-6R-C2-(2-(4-Fluoro-3-methylphenyl)-4,6-dimethylphenyl)-ethenyl3-5(R)-fluoro-4(S)-hydroxy-3,4,5,6-tetrahydro-2H-p ran-2-one E-6R-C2-(3-(4-Fluorophenyl)-1-isopropyl)-1H-indol-2-yl)-ethenyl3-5(R)-fluoro-4(S)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one E-6R-C2-(1-Phenyl-2-isopropyl-4-(4-fluorophenyl)-1H-pyr rol-3-yl)ethenyU-5(R)-fluoro-4(S)-hydroxy-3, ,5,6-tet rahydro-2H-p ran-2-one E-6R-C2-(2-(4-Fluorophenyl)-4-phenyl-6-isopropylphenyl)- - 28 -ethenyl]-5(R)-fluoro-4(S)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one E-6R-C2-(2-(4-Fluorophenyl )-4-phenyl-6-isopropylphenyl )-ethyl]-5(R)-fluoro-4(S)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one 6R-C1-(2-(4-Fluorophenyl )-4-phenyl-6-isopropylphenoxy)-methyl]-5(R)-fluoro-4(S)-hydroxy-3,4,5,6-tetrahydro-2H-py ran-2-one 6S-C1-(2-(4-Fluorophenyl)-4-phenyl-6-isopropylphenylthio) methyl]-5(R)-fluoro-4(S)-hydroxy-3,4,5,6-tetrahydro-2H-py ran-2-one E-6R-C2-(4-(4-Fluorophenyl)-2-isopropyl-6-phenylpyridin-3-yl)ethenyU-5(R)-fluoro-4(S)-hydroxy-3,4,5,6-tetra-hydro-2H-p ran-2-one E-6R-C2-(4-(4-Fluorophenyl)-2-isoprbpyl-6-phenylpyridin-3-yL)ethyL]-5(R)- Luoro-4(S)-hydroxy-3 4 5 -6-tetra-hydro-2H-pyran-2-one E-6R-[2-(4-(4-Fluorophenyl)-6-isopropyl-2-phenylpyrimidin 5-yl)ethenyl]-5(R)-fluoro-4(S)-hydroxy-3,4,5,6-tetra-hydro-2H-pyran-2-one E-6R-C2-(4-(4-Fluorophenyl)-6-isopropyl-2-phenylpyrimidin 5-yl)ethyl]-5(R)-fluoro-4(S)-hydroxy-3,4,5,6-tetra-hydro-2H-pyran-2-one E-6R-[2-(2,5-di-tertiary-butyl-4-phenyl-3-thienyl)-ethenyl]-5(R)-fluoro-4(S)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one (The numbering is in accordance with the pyran nomenclature) The inhibition of HMG-CoA reductase activity by the compounds of the general formulae I and II was determined on solubil ized enzyme preparations from rat liver microsomes.

After changeover of the day/night rhythm of the rat, enzyme formation was induced with cholestyramine (( R ) Cuemid). The substrate used was (S,R)-14C-HMG-CoA, and the concentration of NADPH was maintained during the 14 incubation by a regenerating system. C-mevalonate was - 29 -removed from the substrate and other products (for exam-pie C-HMG) by column elution, with the elution profile of each individual sample being determined. "^H-mev a I on a t e was not always included in the determination because relative data on the inhibitory effects were required. In each series of tests, the enzyme-free control, the e n z yme- c on t a i n i ng normal mixture (= 100%) and those with additions of product were treated together. Each individual value was the mean formed from 3 parallel samples. The significance of the mean differences between product-free and product-containing samples was assessed using the t test.

Using the method described above, the values given in Table I for the inhibition of H G-CoA reductase were determined for the compounds according to the invention C I C 5 Q value M = molar concentration of the compound necessary for 50% inhibition. In each case the I C 5 Q values for the optically pure compounds I in the pre-ferred absolute configuration are given).

Table I Compound of IC50 value E ample 12 2 x 10"6 18 3.2 x 10"8 35 8.5 x 10"9 41 2.0 x 10~8 42 3.6 x 10"8 43 6.3 x 10"9 44 9.8 x 10"8 In addition, the nhibition of cholesterol biosynthesis in cell cultures was tested with selected compounds by the incorporation of 14C-pr ecursor in cholesterol.

Monolayers of HEP G2 cells in I ipoprote in-free nutrient medium were incubated with various concentrations of the test substances for 1 hour. After add i t ion of the - 30 - C-labeled precursor sodium C-acetate, the incubation was continued for 3 hours. Then ^H- c h o I e s t e r o I was added as internal standard, and some of the cells were hydro-lyzed with alkal i. The lipids were extracted from the hydrolyzed cells using chlorof orm/methanol . Carrier cholesterol was added to this l ipid mixture which was then subjected to preparative thin-layer chromatography, the cholesterol band was visual ized with iodine vapor and 14 then isolated, and the amount of C-cholesterol formed 14 from the C-precursor was determined by scintigraphy. Cellular protein was determined in an aliquot of the cells, so that it is possible to calculate the amount of 14 14 C-cholesterol formed from the C-precursor per mg of cellular protein in unit time. The solvent control is used for ' comparison with the inhibitory effect of an added test product, so that the inhibition of cholesterol biosynthesis at a particular molar concentration of the test product in the medium can be stated. The absence of cell damage due to the action of the products was con-f irmed in an al iquot of the cell culture by the morphology (light microscope) . The I C 5 Q values of the test products are stated in mol/l (in Table II), and their relative potencies are compared with mevinol in sodium salt and mevinol in lactone (comparison of the I C 5 Q values).

Table II Compound of Ic50 vaLue f°r inhibi- Example tion of biosynthesis [mol/l] 12 5.5 x 10"6 18 3.2 x 10"7 38 2.5 x 10"7 34 1.1 x 10"7 The compounds of the general formulae I and II are distinguished by potent inhibition of HMG-CoA reductase, the rate-determining enzyme of cholesterol bios nthesis. The enzyme HMG-CoA reductase is widespread in nature. It catalyzes the formation of mevalonic acid from HMG-CoA. - 31 - This reaction is a central step in cholesterol biosynthesis (cf. J.R. Sabine in CRC Series in Enzyme Biology: 3-Hydroxy-3-methy Iglutaryl Coenzyme A Reductase, CRC Press Inc. Boca Raten, Florida 1983 (ISBN 0-8493-6551-1)) A connection is drawn between high cholesterol levels and a number of disorders such as, for example, coronary heart disease or arteriosclerosis. Hence the lowering of elevated cholesterol levels is an aim of therapy for the prevention and treatment of disorders of these types.

One approach to this is the inhibition or reduction of endogenous cholesterol biosynthesis. Inhibitors of HMG-CoA reductase block cholesterol biosynthesis at an early stage.

The cholesterol-lowering efficacy was investigated in the following test on rabbits Normo I p i dem i c male New Zealand rabbits (weight 3-3.5 kg, 4-6 animals per test group) received the test compounds suspended in a 1% strength aqueous c a r bo x yme t h I c e 11 u I o s e solution ( ( R ) Tylose) by gavage each day in the morning; the control group recei ed only Tylose solution. Venous blood was taken every 3 to 4 days 20 hours after the oral administration of the solutions. The total cholesterol content in these samples was determined enzyma t i c a 11 y using the Boehringer Mannheim assay kit ( CHOD-PAP-h i gh performance method). The serum cholesterol level in the group treated with test compounds was compared with that in the control group. The treatment period was followed by a period in which the test compounds were no longer administered.

In this test, administration of the compound from Exam-pie 34 (10 mg/kg/day) resulted in a 40% lowering of total cholesterol within 3 days, and this remained constant throughout the ad inistration without eliciting abnormal or pathological changes in the liver enzyme levels. The serum cholesterol levels returned to their initial value - 32 -within 3 days after discontinuation of the product (after 10 days ) .

Hence the compounds of the general formulae I and II are suitable as hypolipidemics and for the treatment or prophylaxis of arteriosclerotic changes.

Hence the invention also relates to pharmaceutical products based on these compounds, and to the use thereof as medicaments, especially as hypolipidemics and for the prophylaxis of arteriosclerotic changes.

The compounds of the formulae I and II are used as hypolipidemics or a n t i -a r t e r i o s c I e r o t i c s in oral doses of 3 to 2500 mg, but preferably in the dose range 10 - 500 mg. These daily doses can, wherever required, also be divided into two to four single doses or be administered in sustained release form. The dosage regimen may depend on the type, age, weight, sex and medical condition of the patient.

An additional c ho I es t e r o I - I owe r i ng effect can be achieved by concurrent administration of the compounds according to the invention with substances which bind bile acids, such as, for example, anion exchanger resins. The increased excretion of bile acids results in an enhanced neosynthesis and thus in an increase in cholesterol break down (cf. M.S. Brown, P.T. Koranen and J.C. Goldstein, Science 212, 628 (1981); M.S. Brown, J.C. Goldstein, Spektrum der Wissenschaft 1985, 96).

The compounds according to the invention can be used in the form of the δ -lactones, as the free acids or in the form of their physiologicall acceptable inorganic or organic salts or as esters. Acids and salts or esters can be used in the form of their aqueous solutions or sus pensions, or else dissolved or suspended in pharmacologically acceptable organic solvents such as monohydric or polyhydric alcohols such as, for example, ethanol, - 33 -ethylene glycol or glycerol, in triacetin, in alcohol/ acetaldehyde diacetal mixtures, oils, such as, for example, sunflower oil or f ish l iver oil, ethers such as, for example, diethylene glycol dimethyl ether or polyethers such as, for example, polyethylene glycol, or in the presence of other pharmacologically acceptable polymeric vehicles such as, for example, pol inylpyrrol idone, or in sol id formulations.

The preferred pharmaceutical forms for the compounds of the formulae I and II are solid, can be administered orally and may contain the customary auxiliaries. They are produced by customary methods.

Particularly suitable formulations for oral use are tablets, coated tablets or capsules. One dosage unit preferably contains 10 to 500 mg of active ingredient.

Example 1 4,6-0-Benzyl i dene-ct-D -me t h y Iglucos ide (Scheme 1, formula XXIV) 2.3 mol (446 g) of a-methylglucos ide (Scheme 1, formula XXIII) were dissolved in 4.6 I of dry DMF, 3.0 mol (455 g) o . benzaldehyde dimethyl acetal and 0.023 mol (4.4 g) of p- t o uene s u I f on i c acid monohydrate were added, and the mixture was maintained at 90°C and 40 mm Hg, with exclusion of moisture and methanol being distilled out by means of a distillation apparatus, for 12 hours.

After cooling and addition of 60 g of NaHC.03, the mixture was vigorously stirred for 1 h, the precipitate was f iltered off with suction, the solvent was removed by distillation, the residue was taken up in dichloromethane, and the solution was washed with saturated NaHC(>3 solution. The organic phase was then dried with NajSC^ and filtered. The f iltrate was concentrated and then the residue was triturated with petroleum ether, filtered off with suction and washed copiously with petroleum ether. - 34 - 519 g (1.84 moL) (corresponding to an 80% yield) of white solid were obtained, melting point 162 - 163°C (EtOH) .

Ex amp I e 2 2,3-Di-0-mesyl-4,6-0-benzyl idene-ct-D-methylglucoside (Scheme 1, formula XXV) 1 mol (282 g) of the compound from Example 1 was dissolved in 2.5 I of methylene chloride, and 2.5 mol (253 g) of triethylamine and 0.14 mol (17 g) of 4-dimethylamino-pyridine were added. 2.5 mol (286 g) of mesyl chloride were added dropwise to this solution at 0°C, with exclusion of moisture, and the mixture was stirred at this temperature for 2 h and then at room temperature for 2 days.

The organic phase was then washed 2 x with 1.25 I of water, dried over NagSC^ and concentrated. The residue was triturated with methanol, filtered off with suction and dried. 390 g (0.89 mol) = 89% of white solid were obtained, melting point 189 - 190°C (MeOH).

B-NKR (200 MHz, CDClj): «J« 3.0 (e; 3H, S02CB3), 3.2 (e; 3H, S02CH5), 3-5 (B; 3H, OCHJ), 3-7 - 4-0 (m; ABM System; 3H, 6-H2and 5-B); 4.33 (dd, «J- 4.0 Bz, J- 9,0 Bz; 1B, 4-B); 4.65 (dd, J- 4.0 Bz, J- 9,0 Bz; 1B, 3-H); 4.9-5.2 (m; 2H, 2-B a n d 1-B), 5-56 (e; 1B, 0-CH-O) ; 7.3-7-5 (n>; 5-B, Aryl-B).

E ample 3 2,3-Anhydro-4,6-0-benzyl idene-o-methyl-D-alloside (Scheme 1, formula XXVI) 1 mol (439 g) of the compound from Example 2 was dissolved in 6.5 1 of methylene chloride, 8 mol (432 g) of sodium methanolate were added, and the mixture was re-fluxed until reaction was complete, about 3 h (TLC: c c I ohex ane : e t hy I acetate: toluene = 1:2:1, Rf(XXVI) = 0.47). The solution was then washed with water, dried over Na2S04 and concentrated. The residue was tr turated with ether, and the precipitate was filtered off with suction and dried (80°, 1 mm Hg). - 35 - 209 g (0.79 mol) = 79% of a white solid were obtained, melting point 201 - 202° (acetone). 1H-NMR (60 KHz, CDClj): «= 3-5 (e; 3H, OCHj), 3.4-4.5(m; 6H, 2-H, 3-H, 4-H, 5-H, 6-H2), 4.8 (d, J« 2.0 Hz; 1H, 1-H); 5-6 ( B; 1.H, Benzylidene-n ) ; 7.2-7.6 (m; 5H, Aryl-H).

Example 4 3-0-Benzyl-4,6-0-benzylidene-2-deoxy-ct-methyl-D-allo-pyranoside (Scheme 1, Formula XVII) The compound was prepared by known processes in two stages from the compound from Example 3. Lithium alanate reduction, by the method of A.C. Richardson, Carbohydr. Res. 4 (1967) 422, of 1 mol (264 g) of the compound from Example 3 yields 224 g (0.84 mol) = 84% of 4 , 6-0-ben z y I i de ne- 2-deo x y-ct-me t hy l-D-al lopyranos ide of melting point 130 -131°C (EtOH/petroleum ether = 1:4). Alkylation of this compound by the method of Brimacombe (J.S. Brimacombe et al. J. Chem. Comm. Perkin I, 1977, 643) with benzyl bromide in dimethylformamide yielded 207 g (0.58 mol) = 69% of the compound of the formula XVII, melting point 98 -100°C ( eye lohexane ) ; Ca]D = + 63° (C = 0.7, CHCl3). 1H-NMR (200 KHz, [D^-DKSO): 4= 1.9 (ddd t J« 15 Hz, J* 4 Hz, J* 6 Hz; 1H, 2-Η&χ), 2.15 (d B9 (70. eV): m/e= 356 (K+), 324 (K+-CH30H), 91 (Benzyl).

TLC ( eye lohexane : ethyl acetate = 1:1, silica gel 60 F25 O.25 mm, Riedel de Haen): R (XXVI) = 0.28, Rf (XVII) = 0.46.

Example 5 6-0-Acety I -3-0-benzy l-2-deoxy-a-me thy l-D-al lopyranos ide (Scheme 1, formula XIX) - 36 - a) 0.1 mol (35.6 g) of the compound from Example 4 was dissolved in 70 mL of dichloromethane, 3 ml of 70% strength aqueous t r i f I uoroace t i c acid were added, and the mixture was vigorously stirred for 1 hour. TLC ( eye lohexane/ethy I acetate = 1:1): Rf (XVII) = 0.46, Rf (3-0-benzyl-ct-methyl-D-al lopyranos ide) = 0.08. 20 ml of saturated sodium bicarbonate solution were added, and the mixture was stirred vigorously for 10 min. The phases were separated and then the organic phase was dried and concentrated, and the benzaldehyde produced was removed by distillation under high vacuum. 23 g (0.08 mol) = 84% of a colorless oil were obtained. b) The resulting product was dissolved in 320 ml of dichloromethane, 2.5 equivalents of pyridine were added, and the mixture was cooled to 0°C. 0.088 mol (9 g) of acetic anhydride was added dropwise, and the mixture was stirred at room temperature for 12 h. It was then washed with saturated NaHC.03 solution and water, dried and concentrated. Purification was by column chromatography on silica gel, c y c I ohe x an e / e t h y I acetate 1:1. 16 g (0.054 mol) = 67% of XIX were obtained as a colorless oil, R ( eye lohexane/ethy I acetate 1:1) = 0.28. 1H-NMR (270 MHz, CDClj): rf- 1.78 (ddd, J2f2- 15.0, J2f1« 4,5, J2 3" 3f5 Hz; 1B, 2- Eax; 2.10 (e; 3B, COCH^); 2.35 (ddd, J- 15.0 Hz, J2 5- 3.0 Hz, J2 1.0 Hz; 1H, 2-Heq); 2.65 (d, J- 10 Hz; IB, OH); 3-37 ; 3H, OCHj); 3-58 (dt, J5 f 6« 10.0 Bz, J5 4- 4.2 Bz; 1B, 5-H); 3.89 (ddd, 3·0« J5f4- 3.0, J3f2ax- 3.5 Bz; 1B, 3-B); 4.08 (d 4f4- 10.0, J4'5- 4.2, J *3" 3.O Bz; 4-H); 4.34 (m, AB-part; 2H, 6-H); 4.39 and 4.82* (AB-Systen; 2H, Benzyl-CH2); 4.75 (d, J« 4.5 Hz; 1B, 1-B), 7.30-7.45 (o; 5H, Aryl-H).

Example 6 6-0-Acetyl-3-0-benzyl-4-0-deoxy-4-fluoro-ct-methyl-D- gulopyranos ide (Scheme 1, formula XXa) 16 g (0.052 mol) of the compound from Example 5 and - 37 - 0.15 mol (19 g) of ethyldiisopropylamine were introduced under nitrogen into 500 ml of absolute toluene. While stirring at -10°C under Ng, 0.10 mol (16.76 g) of diethylaminosulfur trifluoride ( D AST , Merck-Schuchardt) was added dropwise in such a way that the temperature remained below 0°C. The mixture was then stirred at this temperature for 30 min, allowed to reach room temperature and heated at 80°C for 2 h. Ice-cold saturated NaHC03 solution was added to the vigorously stirred solution at room temperature until no more gas evolution was detectable. The phases were then separated, the aqueous phase was extracted with methylene chloride, and the organic phases were dried and concentrated in a rotary evaporator. Purification was by preparative column chromatography on silica gel ((R)AMIC0N 35-70 μ, 60 A; c y c I oh e ane : e t h y I acetate = 1:1). 9.6 g (0.031 mol) = 59% of a pale yellow oil were obta ined. 1E-ITOR (270 MHz, CDClj): 4- 1.95 (ddd, J2 2" 14*°« J2 3* 5'5, J2 1" 2,0 Hz; 2E» 2~Bax); 2,08 (fldd<3» J2 2" ,0» J2>3« 4.0, , 2Heq); 2.10 (e; 3H| COCHJ); dddd, Jj p« 8.0, J3 2 " J3 2 4.15-4-35 (o; 3Η, 6-H2, 5-B); 3 - 4.0 Hz; 1Η, 4-H); 4.65 (Bc, A 80 (dd, J1 2 2'°> J1 2- 4.5 Hz; 1H, 1-H); 7.25-7.45 (m; 5H, Benzyl-H). Ββ'(70 eV); n/e - 311 (M+-B), 281 (M+-0CH3), 220, 145, 91 , 43.

TLC (silica gel 60, cy c I oh e a ne / e t hy I acetate = 1:1): f (XIX) = 0.28, Rf (XXa) = 0.53.

Example 7 3-0-Tertiary-butyldiphenylsilyl-2,4-dideoxy-4(R)-fluoro-6-deoxy-6- i odo-ot-me t h y I -D-gu I opy r anos i de (formula VII with R2 = C H3 and R20 = t-BuPf^Si) a) 6-0-Acetyl-4-deoxy-4-fluoro-ct-methyl-D-gulopyranoside 19.5 g (0.062 mol) of the compound from Example 6 in 30 ml of methanol were mixed with prehydrogenated - 38 -catalyst, 10% Pd/charcoaL, 2.0 g , and hydrogenated under atmospheric pressure in a shaken vessel until 1.4 I of had been absorbed; TLC (cyclohexane: ethyl acetate = 1:1): Rf (XXa) = 0.51, Rf (product) = 0.27. The catalyst was removed by filtration, and the filtrate was concentrated. 12.9 g (0.058 mol) = 93% of a colorless oil were obtained.

H-NMR (270 MHz, CDClj): rf- 1.9 (d, J- 14 Hz; 1H, 2-HAX), .10 (s; 3H, OAC); 2.18 (dddd, J- 15 Hz; J-J-J- 4-0 Hz; H, 2-Heq); 3.40 (s; 3H, OCHj); 3-60 (d, J- 10 Hz, 1H, OH); .04 (m (br); 1H, 3-H) ; 4.13-4-38 (m; 3H, 5-H, 6-H2); .49 (dd, J- 48 Hz, J- 4 Hz; 1H, 4-H) ; 4-90 (d, J- 4 Hz; H, 1-H); 6-0-Acetyl-3-0-tertiary-butyldiphenylsilyl-2,4-di-deoxy-4-fluoro-a-methyl-D-gulopyranoside 21 mmol (4.9 g) of the alcohol from stage a which had been dr ed over CaCl2 were dissolved in 50 ml of absolute DMF, 11 ml of t r i e t h y I a m i n e were added and, under nitrogen, 1 g (8 mmol) of 4-OMAP was added, and the mixture was stirred at RT. To this were added drop-wise 1.5 equi alents (0.032 mol, 8.43 ml) of tertiary-butyldiphenylchlorosilane. The mixture was left to stir at room temperature for 15 hours and then heated at 90°C for 6 h. It was then evaporated to dryness, the residue was taken up in 100 ml of C H 2 C 12 ^ and a solution was extracted twice with 100 ml of ice-cold 1 N HCl each time, and once with 50 ml of saturated NaHC.03 solution. The phases were separated, ' and the organic phase was dried over a2S0 and concentrated.

Purification by chromatography on 200 g of silica gel 60, eye lohexane : ethyl acetate (6:1): elution of 200-800 ml. 9.5 g (21 mmol) = 100% of a pale yellow oil were obtained.

TLC ( c y c I ohex ane / e t h I acetate = 6:1): Rf (precursor from stage a) = 0.11, Rf (product from stage b) = 0.49, Rf ( t-BuPhgS i C I ) = 0.74. Ca]0 = +38.5° (c = 1, CHCI3). - 39 - Ή-NMR (400 MHz, CDClj): fc 1.10 (B; 9H, C(CH5)j), 1.71 (ddd, J« 14.6, J2 3- 4.0, J2 2.0 Hz; 1H, 2-Hax), 1.87 (dddd, J- 14.6, ¾,ΐ" 4'5' J2 3" ,0 J2 7* ,5 Bz; 1H» 2-H )f 2.09 (B; 3H, OAC), 3-40 (e; 3H,'oCH3), 4.09 (dddd, J- 8.0, J- 4.0, J- 4.0, J- 5.0 Hz; 1H, 3-H), 4.19 (dd, J6.6" 11 *5' J6,6" 5'5 Hzi 1Η· ^ ' ,28 (dd' J6,6" 11 -5, Jg 5- 7.6 Hz; 1H, 6-Hb)f 4-32 (ddd, J4 p- 48.0, J4^3- 5.0 Hz, J4j5 1.0 Hz; 1H, 4-H) , 4-41 (ddd, J$ y- 31.0, J5|6- 7.0, J5>6-'5.5 Hz; 1H, 5-H), 4.7 (dd, J1f2« ∑!θ Hz,'j1t2 - 4-5 Hz; 1H, 1-H), 7.30-7.50 (m; 5H,'AByl-H), 7.60-7.80 (m; Aryl-H). 1;>C-NMR (100 MHz,COCl3): - 19.14 (e; C(CH3)3 , 20.7 (q, COCH3), 26.7 (q, C(CH3>3), 31.6 (dd, C-2), 54-9 (q, CHj), 63.1 (t, d, J6>H- 131 Hz, J6fP. 6.5 Hz; C-6); 63-6 (dd, J5|H- 146 Hz, J5 P- 17.6 Hz; C-5); 65.6 (dd, JjtB- 156 Hz, Jj'p- 28.9 Hz; C-3); 87.8 (dd, J4>H- 156 Hz, J f'F« 182.3 Hz; C-4); 97.7 (d, Jc>g- 166 Hz; C-1), 133-3, 133-4 (e; C-1'), 127.6, 127.7 (d, C-3'), 129.8, 129.9 (d, C-4'), 13 .6, 135.8 (d, C-2'), 170.60 (B, C-0). 19F-NMR (94.2 KHz, CDClj); 6- 204-87; s (70 eV/1 0*): m/e- 461 (M+), 403 (M+ - C4Hg), 371 (403- CHjOH), 343 (403 - CHjCOOH), 213 ((Ph)2SiOCH3), 199 ((Ph)2SiOH), 177, 135, 43- 3-0-Tertiary-butyldiphenylsilyl-2,4-dideoxy-4-fluoro 6-deoxy-6-iodo-ct-methyl-D-gulopyranoside 17.4 mmol (8.0 g) of the acetate from stage b were dissolved in 17.4 ml of methanol, cooled to 0°, and 0.35 ml of a 1 M solution of NaOMe in MeOH was added The solution was stirred at this temperature for 6 hours and was filtered through 10 g of acidic ion ex ( R ) changer (for example Amberlyst 15), which had pre viously been swollen with methanol, and was then washed with methanol, and was evaporated to dryness. 6.8 g (16.3 mmol) = 94% of a colorless oil were obtained. - 40 - TLC ( c y c I ohe x ane : e t hy I acetate = 6:1): Rf (precursor from stage b) = 0.52, Rf (product from stage a) = 0.25. β) The oil was dissolved in 40 ml of py r i d i ne / d i c h L o r o- methane (1:1), 24 mmol (4.6 g) of p- to I uenesu I fony I chloride were added, and the mixture was stirred with exclusion of moisture for 2 days. It was then concentrated, the residue was taken up in ether, and the solution was filtered and concentrated. The resulting crude product (8.7 g) was reacted further without purification. γ) It was dissolved in 120 ml of absolute 0MF, 36 g (0.24 mol) of sodium iodide were added, and the components were stirred at 110° under nitrogen for 3 hours.

Rf (VII, R21 = CH3, R20 = t-BuPhjSi) = 0.61 (cyclo- hexane/ethyl acetate = 6:1), Rf (VII) = 0.32 (toluene/ cyclohexane = 7:3).

The mixture was then concentrated, the residue was taken up in di chloromethane, and the organic phase was washed with water, dried and concentrated. Purification was by chromatography (silica gel, toluene: cyclohexane = 7:3). The product fractions were concentrated, and resulted in 5.8 g (11 mmol) of pale yellow oil VII (R21 = CH3, R20 = t-BuPh2Si) = 67%.

MS (70 eV): m/e« 528 (M+), 471 (M+-C4H9), 367 (M+-CH30B-Hi ) , 213, 167, 129, 91, 41. 1NMR (270 MHz, CDClj): 1.10 (s; 9H, C(CH3)3), 1.66 (ddd, J2,2C 14*5· J2 3B 4,0 J2,1* 2,0 Hz; 1H» 2~Ha ^» 1,85 (ddd» J='l4.5, J2(3«'8.0, J2 4-5 Hz; 1H, 2-Heq), 3.28 (d, J* 7.0 Hz; 2H, 6-CH2),'3.47 (s; 3H, OCHj), 4-07 (dddd, J3)2* B.O, J3t4«J3t2«J3tF« 4.0 Hz; 1H, 3-H), 4-35 (dt, J5,6B 7,0» J5,V 29,0 z'' 1Η· 5_H)» ,47 (dd» J4 3B 4-°» JA',?' 47,0 Hz;' 1H» "H)» ,71 (dd» J1t2B 4'5' Ji*2" 2,0 Hz; 1H,' 1-H), 7.30-7.50 (m; 5H, Aryl-H), 7.60-7.80 (i; 5H, Aryl-H). - 41 - Example 8 2,4-Dichloro-6-(bis-4-fluorophenylmethyl)thiophenol (formula VIII with X = S, R and R3 = CI, R2 = H, R4 H, R^ = b i s -4- I uo roph en I me t h y I ) a) 2,4-Dichloro-6-(bis-4-fluorophenylmethyl )phenol 6.4 g (34 mmol) of 1 , 2 -d i b r omoe t h ane were added drop- wise to 0.85 g (35 mmol) of magnesium turnings in diethyl ether, and the mixture was refluxed for 1 hour.

This solution was added dropwise to a Grignard solution made from 0.85 g (35 mmol) of magnesium and 6 g (34 mmol) of 4-f I uo rob romoben z ene in diethyl ether, and then 7 g (19.5 mmol) of 4, 6-d i c h I o ro-2- ( 4-f I uo r o- benzoy I )phenol (cf. Houben-Weyl, Methoden der organi- schen Chemie (Methods of organic chemistry), volume 7/2a, 1973) were added, and the mixture was refluxed for 4 hours. It was then hydrolyzed with ice/HCl and extracted with ether, and the organic phase was dried and the solvent was distilled off. 8.3 g (16 mmol) (84%) of product were obtained, and this was dissolved in 500 ml of glacial acetic acid, and 5 ml of concentrated HCl were added. After addition of 1 g of catalyst (10% Pd/charcoal ) , hydrogenat ion was carried out in a shaken vessel until the theoretical amount of hydrogen had been absorbed. TLC check: Rf (Grignard product) = 0.16, Rf (phenol) = 0.38 (cyclo- hexanerethyl acetate = 5:1).

Purification was by chromatography on about 1000 g of silica gel (cyclohexane:ethyl acetate = 5:1). Yield: 6.9 g (83%) of white phenol S (70 eV): m/e- 364 (M+), 269 (M+-95), 161.

H (60 MHz, CDClj): MS : C22H17C12N0S, 451/453 (M+), 416 (M+-C1), 347/349 1H-NMR (CDClj, 60 MHz) : 6 - 3,0 (e, 3H, CEj); 3,5 (s, 3Hf CH5), 5,6 (B, 1E, CH), 6,7 (d, 1H, anom. H), 7,0 (B, 4H, arom. B), 7,1 (e, 4B, arom. B), 7,4 (d, 1E, arom. B) c) S-<4, 6-D i c h I o r0-2- C b i s ( -f I uo ropheny I ) me t hy I ] phenyl> N,N-dimethylthiocarbamate 32 g of the compound from stage b were dissolved in 320 ml of sulfolane and heated under nitrogen at 250°C until reaction was complete (about 2 h) and, after cooling, 100 ml of water were added and the mixture was extracted with ether. The dried organic phase was concentrated, and the product was crystallized from hexane. 25.5 g (80%) of the title compound were obtained, melting point 130-131°C (hexane). 1 B-NMR (CDClj, 60 MHZ) : J - 3-0 (B, 6Bt N(CB5)2); 6.1 (B, 1E, CH); 6.65 (d, 1H, Aryl-H); 6.95 (s, 4H, Aryl-H); 7,1 (B, 4B, Aryl-H); 7,5 (d, IB, Aryl-H). 4,6-Dichloro-2-[bis(4-fluorophenyl)methyl] thiophenol A solution of 6.2 g of S- C 4, 6-d i c h I o ro-2- C b i s ( 4-f I uo ro phenyl )methyl pheny I ] , N-d i me t h y I t h i oc a rba a t e from stage c) in ether was added dropwise, while cooling - 43 - in ice, to a suspension of 0.8 g of lithium aluminum hydride in absolute ether. The mixture was stirred at room temperature for 90 min and was hydrolyzed, while cooling in ice, with 2 N sulfuric acid (pH 3). It was extracted several times with ether, the solution was dried over magnesium sulfate, and the solvent was removed in vacuo. The thiophenol remained as residue (5.3 g of viscous oil, 100% yield) and was pure by TLC (100% toluene, R = 0.66); melting point 95°C.

MS: C19H12C12P2S, 380/382 (M+), 283/285 H-NMR (CDClj, 60 MHz): 4- 4,0 (e, 1H, 5H), 5,6 (e, 1H), Methine-H); 6,55 , J- 2,5 Hz, 1H, aPom.-H), 6.85 (B, 4H, aroE.-H), 6.95 (e, 4H, aroo.-H), 7.25 (d, J- 2,5 Hz, 1H, aPom.-H) Example 9 2,4,6-Tr.ideoxy-6-(2,4-dichloro-6-(bisparafluorophenyl-methyl)phenylthio)-4(R)-fluoro-3(S)-0-tertiary-butyldi-phenyls i I y I -a-me t h y I -D -gu I opy r anos ide (formula IX with X = S, R20 = t-butyldiphenylsilyl, R21 = methyl, R1 and R 3 - CI, R2 and R 4 = H, R 5 = bis-4-fluorophenyl-methy I ) . 1.40 g (0.0037 ol) of thiophenol from Example 8 and 1.40 g (0.0037 mol) of iodide VII from Example 7 were introduced into 50 ml of absolute DMS0, 1.00 g (0.0078 mol) of dry K2CO3 was added, and the mixture was stirred at 50°C for 6 h and then at 80°C for 6 h. It was then concentrated, the residue was partitioned between ether and water, and the organic phase was dried and concentrated in a rotary evaporator. 1.73 g (0.0027 mol) = 73% of a pale yellow oil were obtained; TLC (tolu-ene, silica gel); Rf (title compound IX) = 0.21, Rf (VII, compound from Example 7) 0.19, Rf (thiophenol) = 0.75. - 44 - H-NMR (60 MHz, CDClj): ί - 1.1 (B; 9H, C(CH5)j)f 2.6-3.0 (m; 4H, 2-H2, 6-H2), 3-40 (s; 3H, OCHj), 4.0-4-5 (m; 3H, 3-H, 4-H, 5-H), 4.7 (dd, J- 4.5, J- 2.5 Hz; 1H, 1-H), 6.5 (B; 1H, Benzyl-H), 6.8 (d, J- 4Hz; 1H, Aryl-H), 6.9-7.0 (π>, AA'BB' System and d, J- 4Hz; 9H, Aryl-H), 7.3-7.5 (m; 5H, Aryl-H), 7.6-7.8 (n; 5H, Ayyl-H).

MS (DCI/ isobutane): n/e- 749 ( +'OCH-j) , 575, 378, 199, 93- Example 10 2,4,6-Trideoxy-6-(2,4-dichloro-6-(bisparafluorophenyl-methyl)phenylthio)-4(R)-fluoro-3(S)-0-tertiary-butyl-diphenylsiLyl-D-guLopyranose (formula X w th X = S , R 2 ^ = t-C H9Ph2Si, R1 = R3 = CI, R2 = R4 = H, R5 = bis-4-fluorophenylmethyl ) . 1.25 g (0.0016 mol) of lactol ether from Example 9 (formula IX) were introduced into 40 ml of t e t r a h yd r o f u r a n , and 10 ml of water and 12 ml of concentrated hydrochloric acid were added, and the mixture was stirred at 60°C for 10 h. It was then neutralized with solid NaHC03, insolu-bles were removed by filtration, and the filtrate was concentrated in a rotary evaporator. The remaining oil was purified by chromatography (200 g of silica gel 60, eye lohexane : ethyl acetate = 4:1). 413 mg (0.00054 mol) = 33% of an oil were obtained.

TLC (silica gel 60, c y c I oh e x a ne : e t h y acetate = 4:1): Rf (IX from Example 9) = 0.61, Rf (title compound) 0.32 and 0.33.

^ H-NMR (270 MHz, CDCl^): 1.06, 1.08 (B; 9H, C(CH5)5)f 1.50-2.05 (m; 2H, 2-H2), 2.70-2.90 (m; 2H, 6-H2), 3.90-4.40 (m; 3H, 3-H, 4-H, 5-H), 4.95-5-30 (m; 2H, 1-H and OH), 6.45, 6.46 (B; 1H, Benzyl-H), 6.792nd 6.83 (d, J« 4 Hz; 0.6. end 0.4H, Aryl-H), 6.90-7.05 (m; AA 'BB '-System, Θ-Η, Aryl-H), 7.30-7.75 (m; Aryl-H).

MS (70 eV): m/e= 748 (M+-H20), 709 (M+-C4H9) , 691 (748-C4Hg), 561, 378, 283, 199, 109- - 45 - E x amp L e 11 6-(2,4-Dichloro-6-(bisparafluorophenylmethyl)phenylth o)-4(R)-fluoro-5(S)-hydroxy-3(S)-tertiary-butyldiphenyl-s i I loxyhexano i c acid Lactone (formula XI with X = S, R1 and R3 = CI, R2 and R4 = H, R5 = b i s-4-f I uoro- 20 phenylmeth I , R - t-Bu-Ph2Si) 0.54 mmol (0.413 g) of the hemiacetal from Example 10 in 10 ml of absolute d i c h I o rome t h ane was added dropwise to a suspension of 3.2 mmol (6 equivalents) of N-iodo-succinimide and 0.6 mmol (1 equivalent) of tetrabutyl-ammonium iodide in 10 ml of d i c h I o r ome t hane at room temperature. The reaction was complete after 15 min. The mixture was diluted with 30 ml of d i c h I orome t h ane and extracted with 2x 50 ml of ten percent sodium thiosulfate solution, the organic phase was dried over magnesium sulfate and concentrated, and the product was purified by chromatography (silica gel cy c I ohex ane : e thy I acetate = 4:1). The product fractions (180 - 400 ml) were concen-trated. 333 mg (0.44 mmol) = 81% of a colorless oil were obtained, Rf ( c y c I oh e x a ne : e t h y I acetate 4:1) = 0.40. (m; 10H, Aryl-H).

MS (DCI/isobutane): 765 (M++B); 707 (M+-C4H9), 687 (707-HP), 378 (thiophenol fragment), 309, 225, 198 (100 (Ph)2 + -BuSi0+). - 46 - Example 12 6-(2,4-Dichloro-6-(bisparafluorophenylmethyl)phenylthio)-3 ( R ) , 5 ( S ) -d i hyd ro x y-4 ( R ) -f I uo rohe ano i c acid Lactone (formula I, X-Y = S-CHj, R = 2- ( b i s -4- f I uo r op h e n y I -me t h y I ) -4 , 6-d i c h I o r op h eny I ) . 200 mg (0.26 mmoL) of Lactone from Example 11 were dissolved in 10 ml of THF, and 1.6 mmol (0.094 g = 0.089 ml) of glacial acetic acid and 0.8 mmol (0.252 g) of tetra-buty I ammon i urn fluoride trihydrate were added, and the mixture was stirred at room temperature for 14 h. It was then concentrated, and the residue was taken up in 2 ml of methylene chloride and purified by chromatography (20 g of silica gel 60, c y c I o h e ane : e t h y I acetate = 2:1). The product fractions (240 - 360 ml) were combined: Yield 130 mg (0.25 mmol) = 95%, white solid, melting point 75° (ether); Ca]0 = + 7.3° (C = 1, CHCl3).

Rf ( c c I ohe ane : e t hy I acetate = 1:1) = 0.36. 1H-NMR (270 MHz, CDClj): 2.61 (dddd, J2 2- 17-8, J2 3.0 . J5 F , J2 4- 0.8 Hz; 1H, 2-Η&Χ ) ', 2.86 (ddd, J2,2~ 17*8' J2, m *5· J2,0H" 3*5 Hz; 1H» 2~Heq)» 2,98 (dd, J6f6- 14.6, J6>5- 7.6 Hz; 1H, 6-Hb), 3.02 (ddd, J6 6- 14.O, J6 5- 7.0, J6 p- 1.0 Hz; 1H, 6-Hb), 4.41 (dddd, J3,2" *5» J3.2" J3,4" 4*°· J4,F" 5*° Hz; 1H» 5"B)» 4.45 (dddt, J5f6- 7.0, J5 4- 1.5, J5 p- 31.0 Hz; 1H, 5-H), 4.67 (dddd, J 'p- 47.0, j' y 4.0, 5« 1.5, J4 2- 0.8 Hz; 1H, 4-H), 6.4O'(B ; 1H, Aryl-H), 6.82 (D, J 2.0 Hz; 1H, Aryl-H), 7.00 (AA 'BB' -System, 8H, Aryl-H), 7.44 (d, J 2Hz; 1H, Aryl-H) 19F-NMR (CDClj, CFClj Standard, 282 MHz): 4- -115.83 (tt, J- 6.9, J- 7.0 Hz; 1F, Aryl-F) , -115.92 (tt, J- 6.9, J- 6.9 Hz; 1F, Aryl-F9, -207.25 (ddddd, J- 46.8, J- 30.4, J- 5-1, J- 3-5, J- 3.4 Hz; 1F, 4-F). 13C-NMR (CDClj, 100.6 MHz): «Γ- 34.4 (C-6), 35-2 (C-2, J(13C,F)- 5 Hz), 53.9 (Benzyl-C),65.9 (C-3, J5fP- 28 Hz), 75.8 (C-5, J5fp- 18 Hz), 86.0 (C-4, J4 p- 182 Hz), 115.5, 115.6, * 115.7, 115.8, 128.9, 129-Ί , 130.9, 131.0, 135.7, 138.1, 138.2, 151.7 ( aronatic-C), 167.0 (C-0). - 47 - ExampLe 13 Sodium 6(S)-C2,4-dichloro-6-(bis-4-fluorophenylmethyl)-phenylthio]-4(R)-fluoro-3(S),5(S)-dihydroxyhexanoate (formula II, Na salt) 0.044 mmol (0.0232 g) of lactone 1 from Example 12 was dissolved in 2 ml of ethanol, 0.044 mmol (44 pi of a 1 M NaOH) of sodium hydroxide solution was added, and the mixture was stirred at room temperature for 2 h. It was then evaporated to dryness and dried under high vacuum. 25.0 mg (0.044 mmol) = 100% of sodium salt were obtained as a sol id.

TLC (chloroformimethanol = 4:1): Rf (I) = 0.77, Rf (II sodium salt) = 0.22.

Example 14 3-0-Benzyl-2,4,6-trideo -4(R)-fluoro-6-iodo-ot-methyl-D-gulopyranos ide (formu VII with R20 = benzyl, R21 = CH3, 4(R)-f luoro) .

The title compound was synthesized in analogy to Examples 1 to 7 with the difference that the steps in the synthesis as in Example 7, steps a and b, are omitted. The yield at the corresponding step in the synthesis of Example 7 c, a, B, γ is 60% over three stages. The title compound is obtained as a pale yellow oil.

TLC : R f ( eye lohexane : ethyl acetate = 4:1) = 0.37, f ( toluene/cyc lohexane = 7:3) = 0.11. 1H-NMR (270 MHz, CgDg): rf- 1.55-1.80 (m, ABMX System, AB-part; 2H, 2-B2), 2.93 (dd, Jg g- 11.0, Jg 5- 5.5 Hz; 1B, 6-Ha), 3.18 (ddd, Jg g- 11. θ', Jg 5- 9.0 Hz; J- 1.2 Hz 1H, 6-Hb), 3.23 (e; 3H, OCHj), 3-52 (dddd, J? F- 10.0, J3,2"J3,2"J3,4" ,0 Hz; 1H» 5-H), 4.19 (ddd, J5 F- 30.0, J5tg- 5.5, 5t " 9-0 Hz; 1H, 5-H), 4.27 (o; AB-Syetem; Benzyl-CH2), 4.34 (dd, J4fP- 47.0, J4f3« 4.0 Hz; 1H, 4H), 4.46 (dd, J1>2- 2.5, J1 2- 4.5 Hz; 1H| 1-H), 7.05-7.3 (n>; 5H, aromatic-H). - 48 - Example 15 3-0-Benzyl-2,4,6-trideoxy-4(R)-fluoro-6 -tr iphenylphos-phonio-ot-methyl-D-guLopyranos ide iodide (formula XII with R20 = benzyl, and R21 = CH3). 1.0 g (0.0026 mol) of 6- iodo-D-gulos de from Example 14 and the equivalent amount of triphenylphosphine were stirred while being converted into a melt which was stirred at this temperature (80°C) under until reac-tion was complete. The product was then taken up in a little di chloromethane, and the salt was precipitated by addition of toluene. The salt was filtered off with suction and then dried under high vacuum (1.6 g, 95%).

TLC (CHCI3.CH3OH = 10:1) = 0.41. 1H-NMR (270 MHz, CDClj): MS (70eV): m/e- (515, M+), 262, 183- Example 16 2-Butyl-4,6-dichlorobenzaldehyde (formula X 111 a with Z = single bond, R7 = butyl, R8 = R9 = CI).

The synthesis was carried out in analogy to statements in the literature (Stokker et al., J. Med. Chem. 2_9 ( 1986), 173), starting from 2,4-dichlorobenzaldehyde, reaction with aniline to give the corresponding anilide, conversion into a palladium complex and coupling with butyl-magnesium bromide with the addition of triphen lphosphine. After the coupling was complete, most of the triphenylphosphine was removed by cooling the ethereal reaction solution to -78°C, and analytically p u r e product was obtained by chromatography (silica gel 60, cyclohexane: - 49 -ethyl acetate = 100: 1 ) .

TLC ( eye lohexane/ethyl acetate = 4:1) Rf = 0.56.

H-NMR (60 MHz, CDClj): «Γ- 0.7-1.1 (t, J 6 Hz; 3H, CH3), 1.5 (mc; 4H, CH2-CH2), 2.9 (t, J 7 Hz; Benzyl-CH2), 7.I-7.5 (B; 2H, Aromatic-H), 10.6 (e; 1H, CHO).

Example 17 3-0-Benzyl-7-(2-n-butyl-4,6-dichlorophenyl)-6,7-dideoxy- ( R ) -f I uo ro-a-me t hy I -D-gu L ohep t -6E -enopy ranos i de (formula XIV, R = 2-n-butyl-4,6-dichlorophenyl, R20 = benzyl, R21 = methyl) 1 mmol (0.643 g) of phosphonium salt from Example 15 was dried under high vacuum and then dissolved in 5.0 ml of THF/HMPTA (2:1 v/v), and the solution was cooled to -60°C under nitrogen and 1 mmol of n-BuLi (0.72 ml of an approx. 1.4 M solution in hexane) was added dropwise.

After 30 seconds, after the BuLi addition was complete, 1.5 mmol (0.347 g) of aldehyde (from Example 16) was added dropwise within 1 min, and the mixture was allowed to warm to -10°C in 45 minutes. 20 ml of petroleum ether were added, the mixture was filtered, the filtrate was concentrated, and the product was purified by chroma-tography (silica gel 60, hexane/ethyl acetate = 5:1).

The fractions containing product of Rf = 0.41 (cyclo-hexane/ethyl acetate = 4:1) were collected and concentrated. 215 mg (0.46 mmol) = 46% of colorless oil were obta ined.

TLC: Rf (phosphonium salt, Example 15) = 0.01, Rf (aldehyde from Example 16) = 0.56, Rf (product) = 0.41 ( eye lohexane : ethyl acetate = 4:1).

^H-NMR (270 MHz, CDClj): - 0.92 (t, J- 7 Hz; 3H, CHj), 1.25-1.45 (m; 2H, CH2), 1.45-1.60 (m; 2H, CH2), 2.00 (did, J2>2- 14 Hz, J2t3- 4Hz, J2f1- 2.5 Hz; 1H, 2 Hax), 2.11 (mc; 1H, 2 Heq),'2.63 (dd, J- 6 Hz, J- BH; 2H, Benzyl-H2), 3·43 (β; 3H, OCH^), 3.88 (dddd, F- 10 Hz, J3,2" 4 Hz» J3,2" 4Hz* J3,4" 4 Hz; H» 5~H)» I40- . 5 (m; - 50 - 1H, 5-H)t 4.68 (AB-SyBtem; 2H, Aryl-CH20), 4.69 (dd, J4,F" 7 Hz» J4f3" Hz5 1H» ~H)t 4·89 (3d, J- 4.5 Hz, J1,2= 2,5 Ηζί 1~H>» 5.94 (dd, J6f5= 6Hz, JtBanB«: 16Hz; 1H' 6-H)» 6·64 JtraneB 16 Hz; 1H* 7~Η)· 7·08 (»ϊ 1H, Aryl-H), 7.20-7.40 (m; 6H, Ai»yl-B).

Example 18 7-(2-n-Butyl-4,6-dichlorophenyl)-3(S),5(R)-dihydroxy-4 ( R ) -f I uo r o-E-hep t-6-eno i c acid Lactone (formula I with X-Y = CH=CH, R = 2-butyl-4,6-dichlorophenyl ) .

The benzyl protective group was removed, without saturation of the double bond, using Pearlman's catalyst and as specified in the literature (Prugh et al., J. Org.

Chem. 5_1 ( 1986) 60, 651, 654) using the following procedure: 467 mg (1.0 mmol) of the compound from Example 17 were refluxed in 20 ml of ethanol with the addition of 20% Pd(0H)2 C (100 mg) for 50 hours and, after concentration and chromatography, 168 mg (0.43 mmol) = 43% of the debenzy-lated compound were obtained. This was reacted, without further purification, as in Example 10, and the resulting product (150 mg) was oxidized as in Example 11 by oxidation with N- i odos u c c i n i m i de / 1 e t r abu t y I amnion i urn iodide to give the lactone of the title compound.

TLC ( eye lohexane : ethyl acetate = 4:1) Rf (Example 17) = 0.41, Rf (title compound) = 0.01. 1H-NMR (60 MHz, CDClj): rf= 0.9 (t, J= 7 Hz; 3H, CHj), 1.2-1.6 (m; 4H, CH2-CH2), 2.5-5.1 (m; 4H, 2-H2, Benzyl-H2), 4.3-4.5 (o; 2B, 3-B, 5-H), 4.7 (d, J= 47 Hz; 1H, 4-H), 6.0 (dd, J«= 16 Hz, J= 6 Hz; 1H, 6-H), 6.6 (d, J= 16 Hz; 1H, 7-H), 7.1-7.2 (in; 2H, Aryl-H).

Example 19 2,4,6-Trideoxy-3-0-t-butyldiphenylsilyl-4(S)-fluoro-6-iodo-ct-methy I -D-gu I opy r ano s ide (formula VII with R 20 = t-BuPh2Si, R21 = CH3) - 51 -a) a) Methyl-3-0-benzyl-4,6-di-0-acetyl-2-deoxy-D-gulo- pyranoside (formula XXI, Scheme 1) 3.10 g (10 mmol) of anhydrous sugar XIX from Example 5, 5.25 g (20 mmol) of t r i ph eny I ph os ph i ne and 1.84 g (10 mmol) of anhydrous zinc acetate were introduced under nitrogen into 40 ml of absolute toluene, and the mixture was cooled to 0°C and stirred vigorously (suspension). To this were added dropwise 20 mmol (3.48 g = 3.15 ml) of diethyl a zod i c a rbox y I a t e , and the mixture was allowed to reach room temperature.

Since reaction was incomplete after 4 h, a further 10 mmol of Zn(0Ac)2 and 20 mmol of a z od i c a rbo x y I a t e were added, and the mixture was stirred for 15 h.

Then 40 ml of ether and 10 ml of hexane were added, insolubles were removed by filtration, and the product was purified by chromatography (200 g of silica gel, c c I ohe x ane : e t y I acetate = 2:1). 2.3 g (6.5 mmol) = 65¾ of colorless oil were obtained, Rf (title compound) = 0.47, Rf (XIX from Example 5) = 0.33 (cyclohexane:ethyl acetate = 1:1). 1B-NMR (270 KHz, CDClj): S= 1.95 (mc; 2H, 2-H2), 2.05, 2.10 (B; 6H, COCHj), 3.41 (e; 3H, OCH^), 3.63 (ddd, J3 2=J3 2= J3 4= 4 Hz; 1H, 3-H), 4.12 (mc; 2H, 6-H2), 4.47 (dt, j5't6= 7 Hz; 4= 1 Hz; 1H, 5-H), 4.65 (AB-Syetem; Benzyl-CH20) , 4.79 (dd| J4>3= 4 Hz, J4>5= 1 Hz; 1H, 4-H), 4-93 (dd, J1 >2= 3.5, J1 f2= 1*5 Hz; 1H, 1-H), 7.30-7.45 (n; 5H, Acyl-H). b) The compound from stage a was converted by elimination of the acetate protective groups in analogy to Example 7, stage c/ct and acetylation of the 6-OH group as in Example 5 b into the 6-monoacetate XXII with inverse configuration at C-4 and. was then converted in accordance with Examples 6 and 7 into the 4(S)-fluoro deri- vat ive (a-f luoro) . - 52 - Example 20 6-(2,4-Dichloro-6-(bisparafluorophenylmethyl)phenylthio)-3 ( S ) , 5 ( S ) -d i hydrox y-4 ( R ) -f I uor ohe x ano i c acid lactone (formula I with X-Y = S - C H2 R = 2 , 4-d i c h I o r o-6- ( b i s pa r a- I uorophen I me t hy I ) pheny I ) 4,6-Di-0-acetyl-3-0-benzyl-2-deoxy-ct-methyl-D-gulopyrano-side from Example 19a was converted into the fluoro lactone in accordance with Examples 6, 7, 9, 10, 11 and 12.

Colorless oil, Rf = 0.36 ( c y c I oh e x a ne : e t h y I acetate = 1:1). 1H-NKR (270 MHz, CDCl^) ^ 2.6 (n; 1B, 2-Β¾χ), 9-9 (m, 1H, 2-Heq), 3-0 (m; 2H, 6-H2) 4.4 (m; 1H, 1-H), 6.4 (B 1H, Aryl-H), 6.8 (m; 1Ht Aryl-H), 7.0 (B, AA'BB'- system; BH, Aryl-H), 7.4 (m; 1H, Aryl-H).

E ample 21 3-Hydroxymethyl-2-isopropyl-4-p-fluorophenyl-6-phenyl-pyridine The compound was prepared from the corresponding ethyl py r i d i ne-3-c a rbo y I a t e by reduction with L i A L H . The ethyl py r i d i ne-3-c a rbo y I a t e had been obtained by Michael addition of ethyl 4-methy l-3-ketopentanoate onto 1-phenyl-3-paraf luorophenylprop-2-enone and reaction of the product with ammonium ac e t a t e / F eC 13/ g I ac i a I acetic acid by the procedure of F. Rehberg, F. Krohnke, Lieb. Ann.

Chem. JM7 ( 1968) 91. 14 g (0.039 mol) of ethyl 2- i sop ropy I -4-pa r a f I uo rop he ny I -6-p heny I py r i d i ne-3-c a rboxy I a t e were introduced into 300 ml of absolute THF in a 2 I 3-neck flask and, while excluding moisture, 1.4 g (0.039 mol) of L i A L H were added. The mixture was stirred at room temperature for 4 h until reaction was complete. Then 100 ml of water were cautiously added dropwise, and the mixture was extracted with ether. The ether phase was dried (MgS04 and concentrated and then the product was crystallized from cyclohexane. - 53 - Yield: 8 g (0.025 moL) = 64% of white crystals of meltng point 165°C.

TLC: Rf (ester) = 0.51, R-f (alcohol) = 0.23 (Ethyl acetate : eye lohexane = 1:4).

Example 22 2-Isopropyl-4-parafluorophenyl-6-phenylpyridine-3-alde-hyde (formula XHIb, R 10 = isopropyl, R 11 = p-fluoro-phenyl, R 2 = phenyl, A = CH). 13.3 g (0.062 mol) of pyridinium c h I o r o c h roma t e and 10 g of ground 4 A molecular sieves were introduced into 200 ml of absolute CH2Cl2. 10 g (0.031 mol) of the pyridine alcohol from Example 21 were added at room temperature, and the mixture was then stirred for 1 h until reaction was complete (TLC). 500 ml of dry ether were added, and the mixture was filtered through about 100 g of Florisil (column 4 x 30 cm), washing with 200 ml of CH2 1.2- The combined organic phases were concentrated, and the residue was crystallized from isopropanol.

Yield: 8 g (0.025 mol) = 81% of white needles of melt- ing point 98°C.

^ H-NMR (60 MHz, CDClg) :/ * 1.40 (d, J = 7.0 Hz; 6H , CH(CH3)2) , 4.0 (hep, J = 7.0 Hz; 1H, CH Me2 ) , 7.6 - 7.0 (m; 8H, Aryl-H) , 8.4 - 8.0 (m; 2H, Aryl-H) , 10.1 (s; 1H, CHO) .

MS (El) : m/e = 319 (M+) , 290 (M+-CHO) , 276 (M^-C H?) . 263 (276 - CH).

Example 23 2,4-Dimethyl-6-parafluorophenylbenzaldehyde (formula XHIa, R^ = pa r af I uoropheny I , Z = single bond, R 8 = o-methyl, R9 = methyl). - 54 - The compound was prepared as described by Stokker, G.E. et at., J. Med. Chem. 29 (1986) 170- 181.

Yield: 79%, melting point 80-81°C (subl ime). 1H-NMR (60 MHz , COC13 ) : Example 24 2-para-fluorophenyl-6-isopropyl-4-phenylbenzaldehyde. 7 8 (Formula Xllla, R = isopropyl, Z = single bond, R = o o-pa r a- I uoropheny I , R = phenyl).

The compound was prepared from 4-phe ny I benz a I de h y de (Aid-rich) by r epea t ed t r i pheny I phosph i ne-c a t a I y zed addition of 4-f I uoropheny I magnes urn bromide and isopropylmagnes-ium bromide onto the palladium acetate of the appropriate anilineimine by the method of Murahashi, J. Org. Chem. 43 (1978) 4099, as described by Stokker, G.E., J. Med. Chem. 29 (1986) 170-181.

Yield: 75%, white needles of melting point 109-110°C. 1H-NMR (60 MHz , CDClg ) : 1.30 ( d , J 0 7.0 Hz ; 6H , CH( CH3 )2 ) ; 3.90 Tsept. , J = 7.0 Hz, 1H , CH( CH3 )2 ) , 7.70 - 6.70 m; 11H , Aryl-H , 9.75 (s; 1H, CHO).

Example 25 4,6-0-Benzylidene-2-deoxy-3-0-paramethoxybenzyl-ct-met D-a 11 opy ranos i de (formula XVII, R2<"* = p-me t hox ybe n z y I R21 = methyl). - 55 - 150 g (0.56 moL) of 4 , 6-0-ben z y I i dene-2-deo x y-ct-me t h y I -D-a I I opy ranos i de from Example 4 were added in portions to 70.0 g ( 1.6 mol) of a 55% suspension of sodium hydride in mineral oil in 3.8 I of absolute DMF at room tempera-ture (also abbreviated to RT) under nitrogen, and the mixture was stirred at 45°C for 30 m i n and then cooled to RT, and 107.0 ml ( 123.6 g = 0.79 mol) of para-methoxy-benzyl chloride were added dropwise. The mixture was stirred at 80°C for 3 h , allowed to cool, 30 ml of water were added cautiously, and the solvent was removed by distillation under high vacuum (0.1 mm, 40°C) . The residue was dissolved in methylene chloride and washed with water. The organic phase was dried ( M g S 0 ) and concentrated. The residue was crystallized from di isopro-pyl ether. 190 g (0.49 mol) = 87% of colorless crystals were obtained, melting point 85 - 86°C. Rf (product) = 0..49, Rf (precursor) = 0.27 ( c y c I o he x ane : ethyl acetate = 1 : 1) . C 3p° = + 42.7°, c = 1.15, CHCI3.

H-NMR (270 MHz, CDClg) : tf = 1.90 (ddd, J = 15 Hz, J = 4 Hz, J = 6 Hz; IH, 2-Hax ) , 2.17 ( dd , J = 15 Hz, J = 3 Hz; IH, 2-Heq) , 3.40 (s; 3H , 1- oC-OCHg) , 3.60 - 3.75 (m; 2H, 6-H2) , 3.80 (s; 3H, Aryl-0CH3) , 3.94 (ddd, J = J = 3 Hz, J = 4Hz; IH, 3-H), 4.31 (dd, J = 10 Hz, J= 6 Hz; IH, 4-H) , 4.43 (m; IH, 5-H ) , 4.70 (d, J = 5 Hz; IH, 1-H) , 4.75 (AB-System; 2H, Aryl-CHg) , 5.56 (s, IH, benzylidene-H),6.85 and 7.30- (AA'BB'-System; 4H) , 7.30 - 7.60 (m; 5H , Aryl-H).

Example 26 2-Deoxy-3-0-paramethoxybenz l-a-methy l-D-al lopyranoside (formula XVIII, R20 = p-me t ho y ben z y I , R21 = methyl) . 0.19 g (0.001 mol, i.e. a 1 mM solution = 0.02 % by weight solution) of p-toluenesulfonic acid monohydrate was added to 50 g (0.13 mol ) of the benzylidene acetal from Example 25 in one liter of absolute methanol at room temperature and stirred for 20 h. The mixture was neutral ized with 5 ml of t r i e t h I am i ne and concentrated in vacuo. The product was purif ied by column chromatography - 56 - (siLica gel 60, cyclohexane.ethyl. acetate = 1:4 (1.2 L), ethyl acetate (2 I)). 38 g (0.127 mol) = 98% of an oil were obtained. Rf (product ) = 0.17, Rf (precursor) = 0.62 (cyclohexane:ethyl acetate = 1:4). Ca]20 = 146.3°, c = 1.0, C H C 13. 1H-NMR (270 MHz, CDC13) : H-NMR ( 270 MHz, CDClg):/* 1.77 (ddd, J = 15 Hz, J = 4.5 Hz, J = 3.5 Hz; 1H, 2 Hax ) , 2.10 (s; 3H , C0CH3), 2.33 (ddd, J = 15 Hz, J = 3 Hz, J = 1 Hz; 1H, 2-Heq) , 2.64 (d (br), J = 10 Hz; 1H, OH) , 3.38 MS (DCI, i sobutane): m/e = 341 (M-H) , 310 (M-CH OH) , 295 Example 29 2,4-Dideoxy-4(R)-fluoro-3-0-paramethoxybenzyl-a-methyl-D-guLopyranos ide 88.7 m L of a 1 M methanolic solution of sodium methylate were added to 26.9 g (0.079 mol) of the 6-0-a c e t y I gu I o-pyranoside from Example 28 in 320 ml of absolute methanol at RT, and the mixture was stirred for 1 hour. 100 ml ( D ) of the weakly acidic ion exchanger Amberlite CG 50-11 were then added to the solution, which was stirred vigorously for 2 min and f iltered. The residue on the f ilter was washed with methanol, and the combined solutions were concentrated. 21.4 g (0.071 mol) = 90% of a colorless oil were obtained, Rf (product) = 0.23, Rf (precursor) = 0.43 (cyclohexane:ethyl acetate = 1: 1). Ca^0 = +76.5°, c = 1.0, CHCl3. 1H-NMR (270 MHz, CDC13) : = 1.95 (ddd, J = 15 Hz, J = ,5 Hz,' J = 3 Hz; 1H, 2-Hax ) , 2.05 (dddd, J = 15 Hz, J = 5 Hz, J = 5 Hz, J = 3 Hz; 1H, 2-Heq) , 3.41 (s; 3H , d, - OCH3) , 3.70 - 3.92 ( m , 6H, 3-H , 6-H2 and Aryl 0CH3) , 4.19 (ddd, J = 32 Hz, J = 8 Hz, J = 4 Hz; 1H, 5-H ) , 4.49 (dd, J = 46 Hz, J = 5 Hz; 1H, 4-H) , 4.56 (mc > AB- System; 2H , Aryl-CH20) , 4.81 (dd, J = 3.0 Hz, J = 2,5 Hz; ΙΗ, οέ -1-H) , 6.90 and 7.30 ( AA ' BB ' -System ; 4H, Aryl — H ) . - 59 - Example 30 2,4,6-Trideoxy-4(R)-fluoro-6-iodo-3-0-paramethoxybenzyl-ct-methyl-D-gulopyranos ide (formula VII, = para-methox benzyl , R 21 = methyl). 10.5 g (0.035 mol) of 4 ( R ) -f I uo r o-3-O-p-me t hoxybenzy I -ct- e t hy I -D-gu I opy r anos i de from Example 29 were dissolved in 150 ml of absolute DMF, 11 ml of pyridine were added and, at -20°C under argon, 24 g (0.053 mol) of methyl-triphenoxyphosphonium iodide were added with exclusion of moisture. The mixture was stirred at this temperature for 3 hours. A polar intermediate was produced, R- ( c y c I ohex ane : e t hy I acetate = 1:1) = 0.16. The mixture was allowed to warm to RT and then stirred for 2 hours, resulting in the main product with Rf = 0.56, f (precursor) = 0.21 ( c c I ohe ane : e t hy I acetate = 1:1). 15 ml of methanol were added dropwise at 0°C and, after 30 min, the mixture was concentrated in vacuo (< 0.1 mm, 40°C). The residue was taken up in ether, and the solution was washed with ice-cold 1 N sodium hydroxide solution, 10% strength Na2S203 solution and water. The organic phase was dried over Na2SC> and concentrated.

The product was purified by chromatography on 200 g of silica gel (toluene :cyclohexane:ethyl acetate = 7:4:1). 11.6 g (0.028 mol) = 81% of a pale yellow oil were obtained. 1H-N R (270 MHz, CDClg) : = 1,89 (ddd, J = 15 Hz, J = 5 Hz, J = 3 Hz; 1H, 2-Hax ) , 2.01 (dddd, J = 15 Hz, J = 5 Hz, .J = 5 Hz, J = 3 Hz; 1H, 2-Heq) , 3.29 ( d , J = 6 Hz; 2H , 6-H2) , 3.46 (S.; 3H , l-«*-OCH3 ) , 3.70 - 3.85 (m; 1H, 3-H ) , 3.80 (s; 3H, Aryl-OCH3) , 4.22 (dt, J = 6 Hz, J = 30 Hz; 1 H, 5-H ) , 4.58 (dd, J = 47 Hz, J = 4.0 Hz; 1H, 4-H) , 4.55 (AB-System; 2H, Aryl-CHg-O) , 4.79 (dd, J = 4.5 Hz, J = 2.5 Hz; 1 H , <>6 -1 -H ) , 6.90 and 7.30 (ΑΑ'ΒΒ' -S stem; 4H, Aryl-H) .

MS (FAB, 3-NBA , Lil ) : m/e = 417 ( + + L i ) . - 60 - E ample 3 2,4,6-Trideoxy-4(R)-fluoro-3-0-paramethoxybenzyl-6-tri-pheny Lphosphon io-ct-methyl-D-gulopyranos ide iodide (formula XII, R20 = para-methoxybenzyl, R21 = methyl) 9.5 g (0.023 mol) of 6- i odogu I os i de from Example 30 and 15 g (0.057 mol) of triphenyLphosphine were mixed and stirred at 110°C for 4 hours. The mixture was then cooled, dissolved in methanol and extracted once with cyclohexane. The methanolic solution was concentrated and purified by chromatography (Si02, ethyl acetate: methanol = 10:1). 12.5 g (0.19 mol) = 81% of a pale yellow solid were obtained, Rf (product) = 0.02, f (precursor) = 0.79 ( c y c I o h e x ane : e t h y I acetate : 1:1). Rf (product) = 0.43, Rf (precursor) = 0.98 (CHCL^: CH3OH = 4:1). Lal ° = + 8.5°, c = 1.1, CHCI3. 2H-NMR (270 MHz, CDClg) : = 1.78 (ddd, J = 15 Hz, J = 5 Hz, J = 3 Hz; 1H, 2-Hax ) , 2.00 (dddd, J = 15 Hz, J = 5 Hz, J = 5 Hz, J = 3 H z ; 1H , 2- Heq ) , 2.58 (s; 3H, * -1-0CH3) , 3.60 (dt, J = 15.5 Hz, J = J = 11.0 Hz; 1 H, 6-Ha) , 3.78 (m ; 1H, 3-H ) , c 3.80 (s; 3H, Aryl-OCH3)', 4.53 (dd, J = 5.0, J = 2.3 Hz; lH,oC-l-H) , 4.67 (AB-System; 2H, Aryl-CHgO) , 4.8 - 4.6 (m; 1H, 5-H ) , 5.22 (dt, J = J = 15.5 Hz, J = 3.5 Hz; 1 H, 6-Hb) , 5.34 (dd, J = 47 Hz, J = 4.5 Hz; 1H, 4-H), 6.87 ( AA 1 BB ' -System ; 4H, Aryl-H) , and .28 7.60 - (m; 15H, Aryl-H) . 7.95 - 61 - Example 32 4(R)-Fluoro-7-(2-isopropyl-4-parafluorophenyl-6-phenyl- 3-pyr idyl )-3-0-paramethoxybenzyl -2,4, 6,7-tetradeoxy-ct- 20 methyl-D-gulohept-6E-enopyranos de (formula XIV, R = 21 para-methoxybenzyl, R = methyl, R = 2-isopropyl-4-parafluorophenyl-6-phenyl-3-pyridyl ) . 18.0 ml of a 1.6 M n-BuLi solution in hexane (0.0288 mol) were added, at -70°C under argon, to 1.9 ml (1.37 g = 0.0136 mol) of d i sopropy I am i ne (distilled over L i A I H ) in 400 ml of THF (freshly distilled over LiAlH^). The mixture was allowed to warm to room temperature, stirred for 5 minutes and cooled to -70°C, and 200 ml of absolute he x ame t h y I phosphor i c triamide ( HMP A ) were added. 10.0 g (0.0149 mol ) of the phosphonium iodide from Example 31, dissolved in 15 ml of absolute THF, were rapidly added dropwise to this solution. One minute after the addition was complete, a solution of 7.1 g (0.0222 mol) of the pyridine aldehyde from Example 22 was rapidly added drop-wise, and the mixture was stirred at this temperature for 30 min. It was then allowed to warm to RT within 45 min. Water was added caut ously, and the mixture was extracted with ether. The organic phase was dried over MgSO^ and concentrated. The product was purif ied by chromato-graphy on sil ica gel (200 g Amicon 35 - 70 μιη, cyclo-hexanerethyl acetate = 19:1). 7.3 g (0.0125 mol) = 84% of pale yellow oil were obtained, R-f = 0.42 (toluene: c y c I ohe ane : e t h I acetate = 7:2: 1), Rf = 0.36 (cyclo-hexane:ethyl acetate = 4:1).

H-NMR (270 MHz, CDClg) : & = 1.36 (dd, J = 7 Hz, J = 2 Hzj 6H, CH(CH- ) , """" £ Example 33 4(R)-Fluoro-7-(2-isopropyl-4-parafluorophenyl-6-phenyl-3-pyridyl)-2,4,6,7-tetradeoxy-D-gulohept-6E-enopyranose (formula XV, = 2- i s op ropy I -4-pa r a f I uo roph e n y I -6-p h e n y I 3-py r idyl) 4.3 g (0.0073 mol) of the D - gu I oh ep t enopy r anos i de from Example 32 were dissolved in 150 ml of acetone and cooled to -20°C, and 150 ml of 27% HCl were added at this temperature. The mixture was then stirred at 0°C for one hour and at RT for three h. It was then neutralized with solid NajCt^, while cooling in ice, and the precipitate was filtered off with suction and washed with acetone. The organic phase was concentrated, the residue was taken up in C H2 L 2 ^ and the solution was washed with water, dried over MgSO^ and concentrated. The product was purified by rec r s t a 11 i z a t i on from toluene. 2.4 g (0.0053 mol) = 73% of white crystals of melting point 180°C were obtained, R- (precursor) = 0.42, Rf (hemiacetal) = 0.15, Rf (product) = 0.04 (toluene:cyclohexane:ethyl acetate = 7:2:1). - 63 - H-NMR (270 MHz, CDCl3) : MS (DCI, isobutane): m/e = 452 (M+H+) , 434 (M+-0H) , 316 (2-isopropyl-3-ethenyl-4-p- f luoropheny L-6-phen Lpyr d ni urn cat on) Example 34 3(S),5(R)-Dihydroxy-4(R)-fluoro-7-(2-isopropyl-4-para-f 1 uo ropheny I -6-phen I -3-p r i d I ) hep t-6E-eno i c acid lactone (formula I, X-Y = E-CH = CH, R = 2- i s op ropy I -4-pa r a -fluorophenyl-6-phenyl-3-pyridyl). 7.6 g (0.017 mol) of the hemiacetal from Example 33, 19 g (0.085 mol) of N-iodosucc inimide and 12.7 g (0.034 mol) of t e t r abu t y I ammon i urn iodide in 380 ml of absolute C H2 C 12 were reacted in accordance with Example 11; reaction time 6 hours. 6.2 g (0.014 mol) = 81% of white crystalline product of melting point 145 - 147°C were obtained. Rf (product) = 0.36, Rf (precursor) = 0.38 (cyclo-hexane:ethyl acetate = 1:1). - 64 - H-N R ( 270 MHz, CDCl3): MS (DCI, isobutane): m/e = 450 (M+H+), 432 (M+-0H), 405 (M+-C02), 316 UV (CH9C1.):A. (lg E) = 254 (4.40), 300 nm (4.15)sh [*U D = + 22.3 °, c = 1, CHC1,. 19 F-NMR (339 MHz, CDClg, CFC13 int. Standard): = - 114.77 (m; IF, Aryl-F), - 203.71 (ddddd, J = 46 Hz, J = 30 Hz, J 6 Hz, J = 6 Hz, H = 3 Hz; 1 F, 4-(R)-F) Example 35 Sodium 3 ( S ) , 5 ( R ) -d h y dro x y- ( ) - f I uo ro-7- ( 2- i sop ropy -4-para-fluorophenyl-6-phenyl-3-pyridyl)hept-6E-enoate (formula II, X-Y = E-CH = CH, R = 2- i s op ropy I -4-pa r a-f I uo ro-pheny I -6-phen I -3-py r i dy I ) ; C0 a in place of CO2H) - 65 - 17.4 mg (3.9 x 10~^ moL) of the Lactone from Example 34 were dissolved in 3.9 ml of analytical grade ethanol, 39 μΐ of 1 N NaOH were added, and the mixture was stirred at RT for one hour. It was then cautiously concen-trated (rotary evaporator), and the residue was taken up in 3.9 ml of water. The solution prepared in this way was used for the enzyme assay (Liver homogenate) and for investigating the inhibition of biosynthesis in HEP-G2 cells. TLC analysis: Rf (lactone) = 0.79, Rf (Na salt) = 0.16 (CHCl3:CH30H = 4:1).

Example 36 3(S),5(R)-dihydroxy-4(R)-fluoro-7-(2-isopropyl-4-para-f I uo r opheny I -6-pheny I -3-py r i dy I ) hep t ano i c acid lactone (formula I, X-Y = CHj-CHj, R = 2- i s op r opy I -4-pa r a-fluorophenyl-6-phenyl-3-pyridyl). 0.5 g of catalyst (10% Pd/C) was prehydrogenated in ethyl acetate for 30 min. 0.100 g (0.22 x 10~3 mol) of lactone from Example 34 was added, and the mixture was hydrogen-ated in a shaken vessel until 5 ml of had been absorbed. The catalyst was then removed by filtration, washing the filter cake with ethyl acetate, and the filtrate was dried (MgSO.,) and concentrated. 0.098 g (2.17 x 10~ mol) = 98% of colorless oil was obtained. Rf (product) = 0.33, Rf (precursor) = 0.33 ( c y c I ohe x a ne : e t h y I acetate = 1:1).

^ H-NMR (270 MHz, CDCl3) : = 1.39 (d, J = 7 Hz; 3H , CH(CH_3)2) , -1.42 (d, J = 7 Hz; 3H , CHiCH^) , 1.70 - 1.88 ( m ; 1H , 6-H ) , 1.92 -2.08 (m; 1H, 6-H) , 2.18 (d, J = 5 Hz; 1H, OH) , 2.59 (ddd, J = 18 Hz, J = 3 Hz, J = 3 Hz; 1H, 2-H) , 2.70 (m; 1H, 7-H ) , 2.88 (ddd, J = 18 Hz, J = 5 Hz, J = 4 Hz; 1H, 2-H) , - 66 - 2.89 (m; 1H, 7-H), 3.37 (hept., J = 7 Hz; 1H, CH(CH3)2), 4.30 - 4.55 (m; 3H , 3-H , 4-H, 5-H ) , 7.10 - 7.50 ( m ; 8H , Ar 1-H ) , 8.10 ( m ; 2H , Ar 1-H ) , MS (DCI, sobutane): m/e = 452 (M+H+), 318 (2-isopropyl 3-ethyl-4-fluoronhenyl-6-phenylpyri dinium cation).

Example 37 5-Formyl-4-isopropyl-6-parafluorophenyl-2-phenyl-1,3-d azine (formula X 111 b , A = N , R 10 = isopropyl, R 11 = para-fluorophenyl, R 12 = phenyl).

The appropriately substituted pyrimidine-5-aldeh .de was prepared from the corresponding ethyl ester by reduction (CH2Cl2, -78°C, Ar, 3 eq DIBAH, 2 h -78°, 0.5 h, 0°C, 77% yield) and subsequent oxidation (CH2Cl2, PCC, 3 h RT, chromatography, 87% yield).

White solid, melting point 119 - 121°C. 1H-NMR (60 MHz, CDC13): J = 1.4 (d, J = 7 Hz; 6H, CH(CH3)3), 4.0 (hept., J = 7 Hz; 1H CH(CH3)3), 7.2 - 8.0 ( m ; 6H, Ary 1-H ) , 8.6 (m ; 2H , Aryl-H), c 10.1 (s; 1H , CHO ) .

The starting material for the ethyl pyrimidine-5-carboxy-late was commercially available benzamidine hydrochloride, together with 4-carboethoxy-2-meth l-5-paraf luoro-pheny lpent-4-en-3-one which was obtained by aldol conden-sation of ethyl isobutyrylacetate and paraf luorobenzalde-hyde. The components were reacted in accordance with the procedure of E.F. Silversmith, J. Org. Chem. 27 (1962) 4090, and the resulting dihydropyrimidine was aromatized by heating with DDQ or Mn02 in toluene. - 67 - Example 38 3(S),5(R)-dihydroxy-4(R)-fluoro-7-C6-parafluorophenyl-4-isopropyL-2-phenyl-1,3-diaz ίη-5-yL ]hept-6E-enoic ac id lactone (formula I, X-Y = E-CH=CH, R = 6-pa r a f I uo rop eny I -4- i s op r op y I -2-ph e ny I - 1 , 3-d i a z i n-5-y I ) . 0.75 g (0.0011 mol) of the phosphonium iodide from Example 31, 40 ml of THF, 1.2 ml of 1.6 M n-BuLi, 0.13 ml of d i i sop r opy I am i ne , 20 ml of HMPA and 0.72 g (0.0025 mol) of the 1,3-diazine aldehyde from Example 37 were reacted in a Wittig reaction as in Example 32, and the further conversion to the lactone was then carried out as in Examples 33 and 34. 194 mg (0.43 x 10-3 mol) = 39% of lactone were obtained, Rf = 0.35 (cyclohexane: ethyl acetate = 1:1). 2H-NMR (270 MHz, CDC13) : H-NMR (270 MHz, CDCl,) : / «= 1. 31 (d, J = 7 Hz; 3H, CH(CH3)2 ) . 1. 33 (d, J = 7 Hz; 3H, CH(CH )2 ) , J = 3 Hz , J = 3 Hz ; 1H , 2 -H) 1. 62 (ddd, J = 18 Hz , 2. 91 (ddd, J = 18 Hz, J = 5 Hz, J = 4 Hz ; 1H, 2 -H) 3. 32 ( hept , J = 7 Hz; 1H, CHMe ) , 4. 30 (m; 1H, 3-H ) , 4. 39 ( ddd , J = 47 Hz , J = 4 Hz , J = 1 Hz ; 1H . 4 -H) 5. 11 (dd, J = 28 Hz, J = 6 Hz; 1H, 5- H) , 5. 53 ( dd , J = 16 Hz, J = 6 Hz; 6-H ) f 6. 80 (d, J = 16 Hz; 1 H, 7-H) , 7. 05 - 7.65 (m; 11H, Aryl-H).

Example 40 3(S),5(R)-Dihydroxy-4(R)-fluoro-7-(2,4-dimethyl-6-para-f I uoropheny I pheny I ) hep t-6E-eno i c acid lactone (formula I, X-Y = E-CH=CH, R = 2,4-d imethy l-6-p-f I uo rop h eny I p h en I ) . 1.0 g (0.0015 mol) of the phosphonium iodide from Example 31 was reacted with 1.85 ml of 1.6 M n-BuLi, 0.9 ml of di-i sopropy I am i ne, 40 ml of THF, 20 ml of HMPA togeether with 0.69 g (0.003 mol) of the substituted benzaldehyde from Example 23 in a Wittig reaction, followed by hydrolysis of protective groups and oxidation of the hemiacetal as in - 69 - Examples 32, 33 and 34. 0.193 g (0.00054 mol) = 36% of lactone was obtained, Rf = 0.44 (cyclo exane: ethyl acetate = 1:1). 1H-NMR (60 MHz , CDCl.j) : / = 2.3 (s; 3H, Aryl-CH3) , 2.6 Example 42 Sodium 3(S),5(R)-dihydroxy-4(R)-fluoro-7-C6-parafluoro-phenyl-4-isopropyl-2-phenyl-1,3-diazin-5-yl3hept-6E-enoate (formula II, X-Y = E-CH=CH, R = 6-p a r a f I uo r op h en 4-isopropyl-2-phenyl-1,3-diazin-5-yl).

The compound was prepared in accordance with Example 35 f rom the lac tone of Example 38 as a 10"^ molar aqueous solut ion.

Example 43 Sodium 3(S),5(R)-di ydroxy-4(R)-fluoro-7-[2-isopropyl-4-phenyl-6-parafluorophenylphenyl]hept-6E-enoate (formula II, X-Y = E-CH=CH, R = 2 - i s op r opy I -4-p h e ny I -6-p- f I uo r 0- - 70 -phenylphenyl ) .

The compound was prepared in accordance with Example 35 from the lactone of Example 39 as a 10 ^ molar aqueous solut ion.

Example 44 Sodium 3(S),5(R)-dihydroxy-4(R)-fluoro-7-[2,4-dimethyl-6-paraf luoropheny Iphenyl ]hept-6E-enoate (formula II, X-= E-CH=CH, R = 2 , -d i me t h I -6-p-f I uo ropheny I pheny I ) .

The compound was prepared from the lactone (Example 40) _2 in accordance with Example 35 as a 10 molar aqueous solution.

Claims

- 71 - HOE 87/F 197 Patent claims A 3-deme t hy I -4-f I uoromeva I on i c acid derivative of the formula I and the corresponding free dihydroxy carboxylic acid of the f ormul a II in w ic Y-X-R denotes A) the group of the formula in which Y-X is the -GHgQ or CHgS group, and R 1 and R 5 are identical or different and denote a) hydrogen or halogen, b) cycloalkyl having 4-8 carbon atoms or a phenyl radical which can be substituted in the nucleus 1 to 3 times by halogen, trifluoromethyl and/or alkyl or alkoxy, each having 1-4 carbon atoms, or c) a straight-chain or branched alkyl radical having 1 to 18 carbon atoms or a straight-chain or branched alkenyl - 72 -radical having 2 to 18 carbon atoms, it being possible for the alkyl and alkenyl radicals in turn to be substituted 1-3 t imes by a) straight-chain or branched alkoxy radicals ha ng up to 10 carbon atoms, or cycloalkoxy radicals having 3 to 7 carbon atoms, or straight-chain or branched alkenyloxy or alkynyloxy radicals having 3 to 6 carbon atoms, 6) halogen, hydroxyl, cycloalkyl having 3-7 carbon atoms, unsubs t i tuted phenyl or ct- or β-thienyl radicals, or phenyl or a- or β-thienyl radicals which in turn are substituted in the nucleus 1 to 3 times by halogen, trifluoromethyl and/or alkyl or alkoxy having 1 to 4 carbon atoms, γ) unsubs t i tuted phenoxy, benzyloxy, or ct- or β-thienyl- oxy radicals, or phenoxy, benzyloxy or a- or β-thie- nyloxy radicals which in turn are substituted in the nucleus 1 to 3 times by halogen, trifluoromethyl and/or alkyl or alkoxy having 1 to 4 carbon atoms, 0 Ί 6 6 δ) the group -0-C-R , where R denotes: a s t r a i g h t- c h a i n or branched alkyl or alkenyl radical having up to 8 carbon atoms, or a cycloalkyl or cycloalkenyl radical, each of which has 3-8 carbon atoms, or an unsubst i tuted phenyl radical, or a phenyl radical which n turn is substituted in the nucleus 1 to 3 times by halogen, trifluoromethyl and/or alkyl or alkoxy having 1-4 carbon atoms, or a 3-pyridyl radical, R and R are identical or different and denote hydrogen, alkyl having 1-4 carbon atoms, halogen or alkoxy having 1-4 carbon atoms, and R^ denotes hydrogen, halogen, alkyl or alkenyl having up to 4 carbon atoms, alkoxy having 1-4 carbon atoms, or phenyl which can be substituted 1-3 times by halogen or C 1-C alkyl, - 73 - B) the group of the formula IV in which X - Y is equal to CH=CH or CHg-CHg, Z represents a s ingle bond or CH2, and denotes a c y c I oa I i ph a t i c hydrocarbon radical having 3 to 7 carbon atoms, a phenyl radical which can be substi tuted in the nucleus 1 to 3 times by halogen, t r i f uo r ome t hy I , alkyl or alkoxy, each having 1 to 6 carbon atoms, or by hy d r o yme t h y I , or denotes a furyl, thienyl or pyridyl radical, it being poss ibl for the heteroaromat i c radicals to be subst ituted 1 to 2 t imes by halogen, t r i f I uo r ome t hy I , alkyl or alkoxy, each having 1 to 6 carbon atoms, and a 0 R and R denote hydrogen, halogen, t r i f I uo r ome t h y I , or alkyl or alkoxy, each having 1 to 6 carbon atoms C) the group of the formula V in which X-Y is equal to CH=CH or CHg-CHg A is equal to CH or N, and 10 R denotes H, s t r a i g h t - c h a i n C-|-C4-alkyl, branched C^-C^-alkyl, t r i I uo r ome t h I or perf luoroisopropyl , 11 R denotes H, s t r a i g h t - c h a i n C-|-C.4-alkyl, branched C3-C6~alkyl, cycloalkyl having 5-8 ring carbon atoms, phenyl which can be subst ituted 1 or 2 times by straight-chain C-|-C3-alkyl, C 1 -C 3-a I ko x , halogen or by tr i f luorometh I ; - 74 - 12 R denotes H, s t r a i g h t - c h a i n C-j-C^-alkyl, branched C3-C$-alkyl, cycloalkyl having 5-8 ring carbon atoms, phenyl which can in turn be substituted 1 or 2 times by s t r a i g h t - c h a i n C -| -03-3 I ky I , trifluoro- methyl, hydroxyl or by halogen, D) the group of the formula VI which X-Y is the CH=CH or CH2-CH2 group denotes the following sequences of atoms a) N -c ( 1H -py r r 01 -2 -yl) b) S -c (2- th ieny I ) c ) C -N ( 1H -pyrrol -3 -yl) d) C -0 (3- ury I ) e) C -s (3- t h i e n y I ) denotes H, straight-chain Ci-C^-alkyl, branched C^-C^-alkyl, t r i f I uo rome t hy I , halogen or phenyl which is optionally substituted 1-2 times by fluorine chlorine or methyl, denotes H, straight-chain C - C 4- a I kyl , branched C^-C^-alkyl, t r i f I uo r ome t h y I , halogen or phenyl, denotes H, cycloalkyl having 5-8 ring carbon atoms, branched C^-C^-alkyl, or phenyl which can in turn be substituted 1-2 times by straight-chain C 1 - C 3 - alkyl, halogen or t r i f I uor ome t hy I , and denotes H, straight-chain C-|-C3-alkyl, branched C.3-C$-alkyl, cycloalkyl having 5-8 ring carbon atoms, t r i f I uor ome t h I , or phenyl which can in - 75 - turn be substituted 1-2 times by straight -chain C i - C 3- alkyl, halogen or t r i f I uo rome t hy I , and R and R together also denote a conjugated unsaturated radical having 4 carbon atoms, so that R and.R form a fused-on aromatic system, as well as the pharmaceutically utilizable salts and esters thereof . A process for the preparation of a compound of the formula I or II as claimed in claim 1, which comprises the fluoro synthon of the formula VII in which R denotes a protective group which is stable to bases and weak acids, R 21 ' denotes an acetal protective group which can be eliminated with weak acid, such as benzyl, methyl or ethyl, and the fluorine atom has either the R or the S configuration,

1. ) a) being reacted with phenol 6- -s-- thiophenols of the f ormul a in which R to R have the meaning indicated for formula I, and X denotes oxygen, -f sulfur, to give the ethers of the formula IX /J where R to R the meanings indicated for formula I, R,20 and R21 have the meanings indicated for formula VII, and X has the meanings indicated for f or ul a VIII, the ethers of the formula IX being hydrolyzed to give the correspond ng hemiacetals of the formula n which R to R have the meanings ndicated for formula I, and R^ has the meanings indicated for formula VII and X has the meanings indicated for formula VIII, c) the hemiacetals of the formula X being oxidized to give the corresponding lactones of the formula XI XI - 77 -in which R 1 to R 5 have the meanings indicated for formula I, and R^ has the meanings indicated for formula VII, and X has the meanings indicated for formula VIII, and the protected hydroxy lactones of the formula XI being converted into the compounds of the formula I (Y-X-R = group of the formula III) where appropriate the resulting compounds of the formula I being converted into the corresponding open-chain dihydroxy carboxylic acids of the for¬ or the salts thereof or the esters thereof, where appropriate resulting salts or esters being converted into the free dihydroxy carboxylic acids or, where appropriate, the free carboxylic acids being converted into the salts or este s, - 78 -a) being reacted with triphenylphosphine to give the phosphonium salts of the formula XII in which R^ and have the meanings indicated or f ormul a VII, b) the phosphonium salts of the formula XII being con verted in a Wittig reaction with aromatic aldehyde of the formula XIII in which R has the meanings indicated for formula I under B to D, into 4- f I uo r o-5 -a r y I e t hene-s ubs t i ■ tuted deme t hy I me va I on i c acid derivatives of the formula XIV in which R has the meanings indicated for formula I under B to D, and R^ and R^ have the meanings indicated for formula VII, 21 ) in a compound of the formula XIV the R acetal function being subjected to acid hydrolysis, and 20 the R protective group being either subjected to acid hydrolysis or removed by oxidation or ι - 79 - eliminated by hydrogenolys i s to give a lactol the formula XV in which R has the meaning indicated for formula I under B to D, d) the compound of the formula XV being oxidized to give a lactone of the formula I in which R has the meanings indicated for formula I under B to D, e) where appropriate a compound of the formula I in which Y-X represents a (-CH=CH-) group being hydrogenated to give a compound of the general formula I in which Y-X represents a (-CH2-CH2-) group, it also being possible for the hydrogenat ion to take place with the compounds of the formulae XIV or XV to give corresponding compounds in which Y-X represents the (-CH2- H2-) group, where appropriate a hydroxy lactone I being converted into the 'corresponding free hydroxy acids II or the salts thereof or, where appropriate, the corresponding ester being prepared from the free hydroxy acids II or from the hydroxy lactone I. "3": A fluoru ynltion of the -formula VII 87037/2 - 80 - . 3-Demethyl -4-f 1 uoromevaloni c acid derivatives defined in claim 1, substantially as hereinbefore described and with reference to any of the Examples. . A pharmaceutical product containing a compound as claimed in claim 1. 5. A pharmaceutical composition for the prophylaxis and therapy of hypercholesterolemia, containing an effective quantity of a compound claimed in claim 1 or 3. C COOHHEENN ZZEEDDEEKK && RRAAPPAAPPOORRlT PP.. OO.. BBooxx 3333111166 ,, TTeell--AAvviivv